Pathophysiology of overactive bladder
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Int Urogynecol J (2012) 23:975–982
DOI 10.1007/s00192-012-1682-6
REVIEW ARTICLE
Pathophysiology of overactive bladder
Mai A. Banakhar & Tariq F. Al-Shaiji &
Magdy M. Hassouna
Received: 16 July 2011 / Accepted: 16 January 2012 / Published online: 7 February 2012
# The International Urogynecological Association 2012
Abstract Overactive bladder (OAB) is a common disorder nocturia [2]. In addition, the ICS classifies OAB as a syndrome
that negatively affects the quality of life of our patients and for which no precise cause has been identified, with local
carries a large socioeconomic burden. According to the abnormalities ruled out by diagnostic evaluation [2, 3]. Never-
International Continence Society, it is characterized as uri- theless, many authorities describe the overactivity during uro-
nary urgency, with or without urge incontinence, usually, dynamic as involuntary detrusor muscle contractions that
with frequency and nocturia in the absence of causative occur while the patient is trying to inhibit voiding. If caused
infection. The pathophysiology of this disease entity varies by a neurological disease, then OAB was referred to as hyper-
between neurogenic, myogenic, or idiopathic factors. This reflexic, and if by a non-neurogenic or unknown cause, then as
paper provides a review of the contemporary theories be- unstable [4]. Whatever definition is adopted, symptomatic
hind the pathophysiology of OAB. bladder overactivity is a very bothersome problem that can
significantly reduce the quality of life of affected individuals.
Keywords Review article: Pathophysiology of overactive Those who are affected with OAB tend to curtail their partic-
bladder . Overactive bladder . Pathophysiology . Review ipation in social activities and to isolate themselves and are
article predisposed to depression [5]. Furthermore, many patients are
often too embarrassed to seek medical treatment which contrib-
utes to difficulties in understanding the disease. It has a reported
overall prevalence of 16% in Europe [6] and 17% in the USA
Introduction [7]. It has been estimated that about 60% of all patients seeking
care from primary care physicians, urologists, or gynecologists
Overactive bladder (OAB) is a term that was initially proposed experience some level of bladder dysfunction [8].
by Wein and Abrams to describe the clinical problem of
urgency and urge incontinence from a symptomatic point of
view [1]. This definition has been the subject of ongoing The pathophysiology of OAB
controversy. Over the last decade, the definition underwent
standardization by the International Continence Society (ICS) The bladder is a sophisticated organ which stores urine until
to be described as urgency, with or without urge incontinence it is appropriate to initiate micturition in response to internal
(dry and wet), usually in the presence of frequency and and external stimuli. Micturition involves the higher brain
cortex; the pons; the spinal cord; the peripheral autonomic,
M. A. Banakhar (*) : T. F. Al-Shaiji : M. M. Hassouna
somatic, and sensory afferent innervation of the lower uri-
Toronto Western Hospital,
Toronto, ON M5T2S8, Canada nary tract; as well as the anatomical components of the
e-mail: drmaibanakher@hotmail.com lower urinary tract itself. Malfunction of any of these com-
T. F. Al-Shaiji ponents may contribute to the symptoms of OAB. The
e-mail: tshaiji@gmail.com bladder might be capable of a limited repertoire of behaviors
M. M. Hassouna in response to disease, and thus, variable pathologic mech-
e-mail: magdy.hassouna@uhn.on.ca anisms may manifest as the same symptom. However, the976 Int Urogynecol J (2012) 23:975–982
similarity of these symptoms suggests that common factors clinically relevant in the human bladder since they mediate
may underlie the instability seen [9]. Common signs the cholinergic-induced contractions of the detrusor [18,
exhibited by unstable bladders include a sudden increase 19]. The relative contribution of the muscarinic receptors
in intravesical pressure at low volumes during the filling may be altered during aging, disease, or neurogenic lesions,
phase, increased spontaneous myogenic activity, fused te- and thus, muscarinic receptor functions may upregulate
tanic contractions, altered responsiveness to stimuli, and mechanisms that normally have little clinical importance
characteristic changes in smooth muscle ultrastructure and contribute to the pathophysiology of OAB [17].
[10]. In addition, examination of the peripheral innervation The sympathetic nervous system stimulates sphincter
and the micturition reflex in different models of OAB closure in the urethra and relaxes the detrusor muscle during
revealed consistent changes including patchy denervation filling [20]. On the other hand, the parasympathetic nervous
of the bladder, enlarged sensory neurons, hypertrophic gan- system is responsible for the contraction of the detrusor
glion cells, and an enhanced spinal micturition reflex [9]. muscle during micturition while simultaneously relaxing
the urethral sphincter [10]. Somatic innervation tends to
maintain active tone in the pelvic floor musculature and
Neurologic factors of OAB provides excitatory innervation to the striated muscles of
the external urethral sphincter [20].
Under normal physiological circumstances, micturition in It is believed that the brain cortex exerts a predominantly
humans occurs in response to afferent signals from the lower inhibitory influence, while the influence of the brain stem is
urinary tract (LUT), and is controlled by neural circuits in facilitatory [10]. Input from the pontine acts as on–off
the brain and spinal cord which coordinate the activity of the switches to shift the lower urinary tract between the two
smooth muscle in the detrusor and urethra with that of the modes of storage and voiding [21]. One region located
striated muscle in the urethral sphincter and pelvic floor dorsomedially within the pontine functions to control mic-
[11]. The LUT is innervated by an integrated afferent and turition and is termed pontine micturition center (Barring-
efferent neuronal complex of peripheral neural circuits in- ton's nucleus) [22]. Another region within the pontine
volving sympathetic, parasympathetic, and somatic neurons located laterally has been identified as the pontine urine
[12]. storage center, which has been suggested to suppress blad-
The sensation of bladder fullness that precedes normal der contraction and to regulate the striated urethral sphincter
micturition occurs through stimulation of stretch-sensitive muscle activity during the storage phase [14]. These two
receptors during the filling phase which activate mechano- regions of the pontine have been labeled as M- and L-
sensitive axons that convey impulses informing the brain regions, respectively, and may represent separate functional
that the bladder is reaching capacity, and thus, bladder systems acting independently [23]. The suprapontine control
contraction is believed to be initiated by these sensory of these regions has not been clarified in detail [24].
stimuli [13]. The bladder afferent pathways consist of two In adults, the process of urine storage and voiding is
types. The first type is called (Aδ) and is mechanosensitive, under voluntary control; however, in infants, these switch-
with myelinated axons, and is activated by both low (non- ing mechanisms function in a reflex manner leading to
nociceptive) and high (nociceptive) intravesical pressures, involuntary voiding [21]. Any disease process or injury to
whereas the second type of afferent (C-fibers) does not the central nervous system (CNS) in adults can disrupt the
respond to bladder distension, possesses unmyelinated voluntary control of micturition and cause the reemergence
axons, and is activated by cold, heat, or chemical irritation of reflex micturition, causing OAB, detrusor overactivity,
of the bladder mucosa [14].These latter afferents are be- and urinary incontinence [14]. Since the CNS control of the
lieved to contribute to micturition in the fetus and neonate LUT is complex, therefore OAB and detrusor overactivity
and when the bladder and/or the micturition reflex is dam- can be seen as a result of a variety of neurological disorders,
aged in adult life [14] but are not essential for normal in addition to changes in the peripheral innervation and
voluntary voiding [15]. A variety of receptor molecules, in smooth and skeletal muscle components [18].
particular muscarinic receptors, are densely packed within The nervous system is designed to ensure that transmis-
the innermost layer of the bladder and have a close associ- sion occurs across synapses with a high degree of efficiency.
ation with the nervous supply to the bladder [16]. Acetyl- Neuroplasticity is the ability of the nervous system to
choline, which interacts with muscarinic receptors on the change transmitters, reflexes, or synaptic transmission in
detrusor muscle, is the predominant peripheral neurotrans- the event of disease or injury [9]. In these events, the
mitter responsible for bladder contraction [5]. Muscarinic afferent neurons in the dorsal root ganglia enlarge, resulting
receptors, found on presynaptic nerve terminals, may be in a shortened delay in the central transmission of the
excitatory or inhibitory [17]. Of the five known muscarinic micturition reflex. Activation of secondary excitatory para-
subtypes (M1 through M5), M3 appears to be the most sympathetic afferents (myelinated Aδ and unmyelinated C-Int Urogynecol J (2012) 23:975–982 977
fibers), which are usually silent, can then trigger micturition fibers maybe plasticity of the dorsal root ganglion cells
[10]. Normally, bladder control is modulated in an inhibito- supplying the bladder manifested by enlargement of these
ry fashion by the diencephalic and cerebral cortex functions, cells and increased electrical excitability [14]. Capsaicin-
the cerebral cortex being responsible for the timing of the sensitive C-fibers have also been implicated in OAB fol-
control [4]. Any neurological pathology encountered in lowing upper motor neuron diseases such as Parkinson's
these regions is known to be a possible cause of bladder disease and multiple sclerosis [14].
overactivity [25]. Cerebrovascular accidents are frequently These afferents can play a role in detecting chemical
associated with symptoms of bladder overactivity. Various stimuli and initiating efferent signals for bladder contraction
cortical lesions are thought to lead to these symptoms due before stretch receptors are activated [38, 39]. This series of
to damage to the cerebral inhibitory centers leading to events may contribute to the urge to urinate at low bladder
uninhibited detrusor contractions [26]. Other cerebral volumes, a symptom characteristic of OAB [13].
infarction-induced factors that may lead to OAB include
alterations in N-methyl-D-aspartic acid glutamatergic mech-
anisms [27], dopamine D2 receptor excitatory mechanisms
Aging
[28], dopaminergic–glutamatergic interactions in the brain
[29], a central mechanism sensitive to nitric oxide [30], and
Changes in neuronal and nonneuronal acetylcholine have
a decreased GAGA-mediated inhibition of micturition [31].
been associated with the aging bladder and may contribute
Other neurological entities that are known to cause OAB
to bladder dysfunction in the form of OAB [13]. Several
syndrome include Parkinson’s disease, multiple sclerosis,
investigators have shown an age-related increase in stretch-
and spinal cord injuries. Parkinson’s disease often results
induced acetylcholine from nonneuronal cells in the urothe-
in detrusor overactivity and an impairment of relaxation of
lium as well as a decrease of neuronal acetylcholine release
the striated urethral sphincter [32]. Detrusor overactivity
in response to electrical field stimulation decreases with
tends to increase with progression and severity of the dis-
aging [13]. Nonneuronal acetylcholine may act in a para-
ease and may be found in up to 90% of patients in the late
crine or autocrine manner to promote detrusor contraction
stages of the disease [33, 34]. It has been suggested that,
[40].
typically, the basal ganglia have an inhibitory effect on the
micturition reflex and that cell loss encountered in the sub-
stantia nigra during Parkinson’s disease will lead to detrusor
overactivity [14]. In multiple sclerosis, OAB is mainly due Bladder outlet obstruction
to spinal lesions, although there maybe contribution from
cerebral lesions [14]. Demyelinating plaques of the white A urologic pathology such as bladder outlet obstruction may
matter of the brain and spinal cord, especially the posterior lead to detrusor overactivity through cholinergic denerva-
and lateral columns of the cervical cord, are the cause of tion of the detrusor and subsequent supersensitivity to
neurological function impairment in multiple sclerosis, and acetylcholine [41, 42]. Furthermore, prolonged outlet ob-
thus, depending on the site of lesions, different pathophys- struction could have an influence through an increased pro-
iological mechanisms may be involved in OAB of patients duction of nerve growth factor, induced neuronal enlargement
with this disease [35, 36]. With spinal cord injury, the degree [43], exerting metabolic effects through the generation of free
of urinary dysfunction is related to the area of the spinal radicals and lipid peroxidises [44], and enhancement of the
cord affected by the disease and the severity of neurological spinal micturition reflex [45]. Relief of obstruction has been
impairment which can involve parasympathetic, sympathet- shown to be associated with the reduction of urinary frequency
ic, and somatic nerve fibers [24, 37]. Damage to the spinal and reversal of these changes [46].
cord above the sacral level results in detrusor overactivity Steers has discussed another possible molecular trigger
which is thought to be associated with the emergence of a for changes in bladder afferents or synaptic transmission in
capsaicin-sensitive C-fiber-mediated spinal micturition re- the CNS secondary nerve growth factor (NGF), which is a
flex caused by a reorganization of synaptic connections in naturally occurring molecule that stimulates growth and
the spinal cord [14]. These C-fibers which are usually silent differentiation of the sympathetic and certain sensory
during a normal state of bladder filling become active during nerves, as well as being responsible for neuronal regrowth
a pathological state and can fire at low pressures, in addition after injury [9]. It has been shown that patients with OAB
to high pressures [18]. During spinal cord injury, the bladder and benign prostatic hyperplasia may have elevated levels
afferents, which normally are unresponsive to low intraves- of nerve growth factor in their bladders, and recent data
ical pressures, become more mechanosensitive, leading to suggest that membrane conductance, and thus excitability
the development of detrusor overactivity [18]. The mecha- of neurons, is altered in models associated with increased
nism underlying the increased mechanosensitivity of C- access to nerve growth factor [9].978 Int Urogynecol J (2012) 23:975–982
Bladder ischemia Inflammatory factors of OAB
Other conditions such as ischemia may injure nerves, lead- As we mentioned earlier in this review, NGF is a molecular
ing to smooth muscle damage and impaired contractility trigger for changes in the afferents or synaptic transmission
[10]. Ischemia of the bladder is often seen in patients with in the CNS and is shown to be elevated in patients with
benign prostatic hyperplasia, urethral stricture, detrusor– OAB. NGF has been found to be elevated in the bladders
sphincter dyssynergia, peripheral vascular disease, and dia- and urine of patients with IC and also in models of bladder
betic neuropathy, all of which may cause severe obstruction, inflammation in animals [52, 53]. Since NGF orchestrates
reduced blood flow, and neuronal death [47, 48]. The coex- events during the growth, maturation, and function of vis-
istence of neurologic factors and ischemia gives rise to the ceral afferents, we could anticipate that inflammation of the
entity of detrusor hyperactivity with impaired contractility urinary bladder would be accompanied by neuroplasticity in
or unstable contractions in the absence of sensation of sensory nerves [9]. Repeated inflammatory stimuli tend to
urgency [49]. elicit enlargement of the bladder dorsal root ganglia neurons
and reduce the activation threshold for bladder afferents
[54]. Likewise, bladder NGF lowers the threshold for blad-
Myogenic factors of OAB der afferents [9]. Inflammation-induced bladder overactivity
can be inhibited by a fusion protein that prevents interaction
One potential cause of OAB has been due to myogenic between NGF and its tyrosine kinase A receptor [55].
dysfunction secondary to altered structure or disordered
function of the detrusor smooth muscle [42]. Normally, the
detrusor is made up of smooth muscle bundles which are not Gender factors of OAB
well coupled electrically, and thus, the bladder is densely
innervated to allow the detrusor to relax when signaled by A number of reviews have suggested that OAB are more
the sympathetic nervous system or contract when signaled common in women than in men and that both conditions are
by the parasympathetic nervous system [10]. The lack of more prevalent at times of changing hormonal levels in wom-
electrical coupling also causes the bladder to ignore irrele- en [56]. This gender difference in the nonelderly population
vant electrical impulses that would otherwise cause an un- may be explained by hormonally induced differences in neu-
warranted response. rotransmitter systems especially 5-hydroxytryptamine (5-HT)
Investigations in human models of detrusor overactivity [9]. Estrogen and progesterone may exert influence effect on
utilizing light and electron microscopy have revealed spe- female nerves [9]. Zhu et al. showed that female hormones
cific structural changes in the bladder wall, including infil- appear to influence bladder contractions and voiding frequen-
tration of smooth muscle by elastin and collagen and patchy cy [57]. In the same context, Nishizawa et al. suggested that
denervation in addition to changes in the cell-to-cell junc- women may be predisposed to OAB in part because levels of
tions that mediate electrical coupling between muscle cells 5-HT in the brain are substantially lower in women than in
[42, 50]. Such changes in the unstable bladder make it better men [58]. On the grounds of reduced 5-HT in the CNS, there
coupled electrically which allows spontaneous electrical may be fewer inhibitory mechanisms for autonomic events
activity to spread and initiate synchronous contractions such as voiding which can predispose women to OAB [9]
throughout the detrusor, which explains the fused tetanic (Table 1).
contractions seen in unstable bladder strips [9]. This in-
creased excitability and greater connectivity of the smooth
muscle create foci of electrical activity that could propagate Psychological factors and OAB
and generate an uninhibited contraction [9]. The sensation
of urgency seen in OAB has also been linked to the stretch- There is growing evidence suggesting that individuals with
ing of small portions of the bladder wall due to the localized depression, anxiety, and attention deficit disorder may ex-
contraction of smooth muscle, leading to activation of a set perience symptoms of OAB more often than the general
of stretch-sensitive neurons that mediate the sensation of population [59, 60]. These conditions appear to be associat-
urgency [51]. Another common feature in unstable detrusor, ed with disturbances in the brain circuits using specific
at an ultrastructural level, is the presence of protrusion neurotransmitters, especially 5-HT which has been shown
junctions and ultraclose abutments between the myocytes to exert a facilitating effect on voiding via modulation of
correlating to the increased electrical coupling of OAB [9]. bladder afferents, volume thresholds, and bladder contrac-
These morphologic changes seen in OAB can be age related tions [10, 59, 61]. Furthermore, some data showed that 5-
or a result of nerve damage from disease, injury, or prolonged HT and its precursors, uptake blockers, or 5-HT analogs
obstruction [40, 43]. inhibit bladder activity in a variety of species [9]. Zorn etInt Urogynecol J (2012) 23:975–982 979
Table 1 Conditions that can cause or contribute to symptoms of overactive bladder, adapted from [5]
Lower urinary tract conditions Mechanisms or effect
In both sexes
Urinary tract infection Inflammation with activation of sensory afferent signaling
Obstruction Obstruction can contribute to detrusor overactivity and urinary
retention
Impaired bladder contractility Urinary retention reduced functional capacity causing frequency
and urge incontinence
Bladder abnormalities or inflammation Intravesical abnormalities can precipitate urgency and urge
incontinence
Neurological conditions: stroke, Alzheimer’s disease, Higher cortical inhibition of the bladder is impaired, causing
multiinfarct dementia, other dementias, Parkinson’s neurogenic detrusor overactivity
disease, multiple sclerosis, normal pressure hydrocephalus,
benign and malignant tumors
Estrogen deficiency Inflammation from atrophic vaginitis and urethritis can contribute
to symptoms other than UI (e.g., local irritation and risk of UTIs)
Sphincter weakness Ability to inhibit detrusor contraction may be diminished
Men
Prostate enlargement Benign obstructive prostate hypertrophy or prostate cancer may
cause urgency, frequency, nocturia, and urge incontinence
al. carried out a study comparing 115 consecutive inconti- Idiopathic OAB
nent patients presenting to an incontinence clinic to 80
continent controls [60]. Patients were queried for a history In idiopathic OAB, the pathophysiology remains elusive.
of depression and completed a Beck Depression Inventory Could this be explained by subtle, subclinical suprasacral
(BDI). A BDI of greater than 12 and/or a history of depres- or cortical defects? Many believe that idiopathic OAB in
sion was noted in 30% of incontinent patients and 17% of children is the result of a maturation delay that resolves over
controls. An abnormal BDI or history of depression was time, and this belief is in contrast to the theory behind OAB
revealed in 60% of patients with idiopathic urge inconti- in adults, in whom the condition is believed to be chronic
nence (P980 Int Urogynecol J (2012) 23:975–982
conditions that may have a common final pathophysiologic LUT and leading to the development of the OAB is not
pathway. This heterogeneous group of conditions could be known?
subdivided on the basis of presumptive etiopathogenesis,
urodynamic patterns, and response to treatment. The diag-
nosis of detrusor instability, its rate of detection, and its Conclusion
urodynamic patterns depend on the type of urodynamic test
used and the way the test is performed. The ICS definitions OAB is prevalent in the population, the etiology of which
of detrusor instability have been called into question by the remains not clearly understood. The pathophysiology of this
results of studies using urodynamic tests in addition to, or disease entity varies between neurogenic, myogenic, or idio-
instead of, provocative cystometry, ambulatory urodynam- pathic factors.
ics, urethrocystometry, the ice water test, and evaluation of
the voiding phase. The literature supports a broadening of
the ICS criteria for excluding all known causes of detrusor
Conflicts of interest None.
instability when establishing the diagnosis of idiopathic
overactive bladder [64].
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