Download neurourologic findings with applicability to incontinence

PROCEEDINGS
NEUROUROLOGIC FINDINGS WITH APPLICABILITY
TO INCONTINENCE AND URETHRAL FUNCTION*
—
Edward J. McGuire, MD
ABSTRACT
Neurourology is applicable to urinary incontinence and obstructive uropathy in the general
population. In most neurogenic conditions, incontinence is related to a loss of coordination of the
bladder with the urethral sphincter mechanism.
This article discusses possible causes and risk factors for stress incontinence and gives several clinical examples of patients with incontinence of
varying causes.
No medications have been approved by the
US Food and Drug Administration for the treatment of stress incontinence. Alpha receptor agonists, tricyclic antidepressants, and estrogen have
all been used to treat the condition, with varying
degrees of success. A new pharmaceutical agent
targeting the unique motor neurons in Onuf’s
nucleus, which specifically innervate the striated
urethral sphincter, shows promise as an effective
treatment for motor urge incontinence and possibly certain types of stress incontinence. The types
of stress incontinence for which the agent may be
effective, however, must be carefully defined.
(Advanced Studies in Medicine. 2002;2(19):681-689)
*This article is based on a presentation given by
Dr McGuire at the 2002 Annual Meeting of the American
Urological Association.
Address correspondence to: Edward J. McGuire, MD,
Department of Surgery, University of Michigan, A. Alfred
Taubman Health Care Center, 1500 East Medical Center
Drive, Room 2918, Ann Arbor, MI 48109. E-mail:
[email protected].
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eurourology, especially the video urodynamic study of urinary tract function
and dysfunction in patients with
known neural lesions, is applicable to
urinary incontinence and obstructive
uropathy in the general urologic population. It was
first established in neurogenic conditions that risk is
related to abnormal bladder compliance or the ability
of the bladder to store urine at low pressure.1 This
abnormality is the result of bladder outlet obstruction. In most neurogenic conditions, this obstruction is related to a loss of coordination between the
bladder and the urethral sphincter mechanism.
Abnormal bladder storage function also results from
any significant obstructive process involving the
bladder outlet, such as benign prostatic hypertrophy
or urethral obstruction after stress incontinence
surgery (Figure 1). Obstruction, structural or neurogenic, has the same effect on compliance, which in
turn determines risk.
N
URETHRAL FUNCTION
According to a body of opinion, urinary continence depends primarily on reflex and volitional contractility of the striated muscle portion of the
urethral sphincter. The part of the urethral closure
mechanism with the highest pressure is the
midurethral area. The function of this area is putatively abnormal in men with postprostatectomy
incontinence and in women with stress incontinence.
Thus, strengthening this area with exercises or direct
electrical stimulation is advocated for both postprostatectomy and stress incontinence.2,3
In women, pelvic floor dysfunction is a broad term
that includes vaginal prolapse conditions as well as uri-
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nary and fecal incontinence associated with childbirth
injuries to the urethral and anal sphincter and the levator musculature during labor and delivery. The term also
broadly includes stress incontinence conditions related
to the same kinds of injury or functional alteration.
Figure 1.Video Urodynamic Study of a 66-Year-Old
Man With Obstructive Uropathy Due to Benign
Prostatic Hypertrophy
CHILDBIRTH AND LEVATOR MUSCLE FUNCTION
Occasionally, labor and delivery are associated with
acute onset of severe stress incontinence, such that
even minimal effort is associated with gross leakage
(Figure 2). Vaginal prolapse and fecal incontinence
also occasionally seem to result from labor and delivery. These conditions were once thought to be transient and to improve with time. All of these conditions
probably do not improve with time, however.
Recovery instead seems to be related to the nature and
extent of the injury.
Magnetic resonance imaging (MRI) studies by
DeLancey et al at the University of Michigan suggest
that serious levator muscle injuries, with partial or
total loss of levator mass can be incurred during childbirth (Figure 3).4,5 These conditions are associated with
vaginal prolapse and incontinence. When severe stress
incontinence occurs immediately postpartum, however, video study shows an open nonfunctional internal
sphincter mechanism or one that leaks at very low
abdominal pressures.
Levator muscle injury and intrinsic sphincter dysfunction do not always occur together. Stress incontinence may occur alone, without levator muscle injury,
and vice versa. Although the mechanism of injury for
both conditions appears to be trauma associated with
labor, levator muscle injuries do not cause stress incontinence; isolated stress incontinence can occur independent of levator muscle injury.
This patient has poor bladder compliance and high-pressure, low-volume
contraction associated with a lack of opening of the bladder outlet and
prostatic urethra.
Figure 2. Severe Stress Incontinence Associated
With Labor and Delivery
There is some mobility of the urethra, but the Valsalva leak-point pressure is 25 cm H2O, which is very low.
Figure 3. MRI Study of the Levator Musculature
URETHRAL FUNCTION ASSOCIATED
WITH CERTAIN NEURAL LESIONS
Specific findings in patients with certain neural
conditions suggest that our ideas about the role of the
striated sphincter in urethral incontinence may not be
completely accurate. Total loss of striated urethral
sphincter activity associated with complete sacral root
transection does not cause stress incontinence per se,
although with time both uterine and other vaginal
prolapse conditions may develop (Figure 4).6 However,
total loss of internal sphincter function associated with
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A
B
A normal woman (A), and a postpartum woman showing absence of
both levator ani muscles (B). Printed with permission from John
DeLancey, MD, University of Michigan.
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specific neural disease or injury does cause severe stress
incontinence, even if normal reflex and volitional
function of the external sphincter are preserved. This
occurs in some patients who sustain a pelvic neural
plexus injury during abdominal-perineal resection for
rectal carcinoma (Figure 5).7 This type of injury is
intrapelvic; thus, the pudendal nerves are spared and
the external sphincter functions normally. This also
occurs occasionally after radical hysterectomy. As in
the former condition, the striated sphincter functions
normally, but the bladder is decentralized and areflexic, and the smooth sphincter is nonfunctional. These
patients have severe stress incontinence.
Unlike sacral cord or root injuries, spinal cord
injury at the 12th thoracic and first lumbar cord levels
is associated with total loss of proximal urethral closure
and severe stress incontinence.8 A similar situation
exists in as many as 85% of patients with myelodysplasia (Figure 6). In patients with myelodysplasia,
some function of the striated sphincter is preserved
(although function is certainly not normal), but there
is no function of the internal sphincter. These individuals have severe stress incontinence. Thus, certain
neural lesions associated with loss of proximal urethral
sphincter function result in severe stress incontinence,
even if the striated sphincter retains function.
A further interesting aspect to these conditions is
that function of the striated sphincter is not linked to
phases of bladder activity as it is in normal states. As a
result of pelvic neural injury, the bladder is decentralized; thus, there is no neural mechanism to support
coordination of the bladder with the striated sphincter.
In this case, persistent closure of the urethra by the
striated sphincter, which is the only part of the urethra
that remains functioning, is obstructive. Depending
on the strength of urethral closure, this obstruction
can induce progressive loss of bladder compliance and
pose a risk to ureteral and renal function. The obstruction induces destructive behavior with a progressive
loss of bladder compliance and higher ambient bladder pressures at progressively smaller bladder volumes
(Figure 7). This happens despite coexistent severe
stress incontinence. The process can be ameliorated by
a surgical procedure that lowers outlet resistance.9
These findings suggest that resistance to abdominal
pressure as an expulsive force is mainly the province of
the internal sphincter.
Loss of internal sphincter function—even if the
striated sphincter functions normally—is associated
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Figure 4.Video Urodynamic Study of a 60-Year-Old
Woman With Continuous Incontinence and No
Sensory Awareness
The patient has severe sacral stenosis and no volitional anal or urethral
sphincter activity. The bladder neck is closed, and she has no stress
incontinence. Her incontinence is caused by detrusor pressure equilibration with urethral resistance; thus, she has continuous leakage. The
expulsive force is detrusor pressure rather than abdominal pressure.
Figure 5.Video Urodynamic Study of a Patient With
Incontinence After Abdominal-Perineal Resection of
the Rectum for Carcinoma
The patient has had a penile prosthesis implanted and a bulbous urethral artificial urinary sphincter. He is severely incontinent and has a nonfunctional internal sphincter mechanism. His incontinence is caused by both a weak proximal
sphincter and a poorly compliant bladder. His upper tracts are at risk.
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with severe stress incontinence. On the other hand,
the bladder faces the totality of urethral resistance (the
highest being in the striated sphincter area) in the
absence of the usual neural mechanism to open the
urethra with detrusor expulsive activity. The bladder
responds to the fixed outlet resistance offered by the
striated sphincter, and compliance progressively deteriorates. A certain degree of resistance is required for
adverse effects on the ureters to be produced (Figure
8). A urethral closure mechanism that requires a detrusor pressure of 40 cm H2O to induce leakage is dangerous to bladder, ureteral, and renal function.
TREATMENT OF INCONTINENCE ASSOCIATED
WITH PROXIMAL URETHRAL FAILURE
Closing the urethra stops stress leakage, but one
does not want to increase the detrusor pressure
required to induce voiding. Obviously, this is not voiding in the sense of coordinated bladder contraction
and urethral relaxation, but leakage across a relatively
fixed striated sphincter mechanism driven by increased
detrusor pressure resulting from increased volume.
Closure of the proximal sphincter is only safe when it
does not change the detrusor–striated sphincter relationship, which determines risk to the upper urinary
tract (Figure 9). Slings are quite safe here, because the
increase in luminal pressure in the urethra after a sling
procedure is less than 10 cm (Figure 10). This is not
true for buried urethral segments or a submucosal
neourethra where the efficiency of the valve mechanism increases with volume and with detrusor pressure, nor for the artificial sphincter placed at the
bladder neck, which can increase the detrusor leakpoint pressure to values above 40 cm H2O.
These findings suggest that a small pressure advantage of the proximal urethra over the bladder is associated with stress competence. The exact role of the
striated sphincter in resistance to abdominal pressure
as an expulsive force is thus difficult to estimate, but
function of the striated sphincter alone, without
smooth muscle closure, does not provide continence.
The striated sphincter clearly has a role as reflex-activated back-up system to prevent stress leakage.
However, whether isolated loss or weakening of striated sphincter function itself causes stress incontinence
remains to be proven. In clearly defined neural conditions, stress incontinence does not result from isolated
loss of striated sphincter activity.
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Figure 6.Video Urodynamic Study of a Boy
With Myelodysplasia
Note the nonfunctional proximal sphincter but closure of the urethra in
the high-pressure zone.
Figure 7. Intravenous Urogram From a 55-Year-Old
Man With a Neurogenic Bladder After AbdominalPerineal Resection for Rectal Carcinoma
Note the open bladder neck but closure of the urethra in the striated
sphincter zone. The upper tracts show the effects of an elevated detrusor leak-point pressure despite severe stress incontinence.
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CONDITIONS ASSOCIATED
WITH ABNORMAL FUNCTION
OF THE STRIATED SPHINCTER
Figure 8.Two Cases of Children With Myelodysplasia
Fowler et al described a
peculiar abnormality of the
striated sphincter in young
women with partial or complete urinary retention.10,11
They recorded specific abnormalities by sphincter electromyography in these women,
clearly indicating that the
inability to initiate detrusor
contraction is related to a neural problem that prevents relaxation of the striated sphincter.
A
B
These patients were previousSevere upper tract dilation is shown in a child with myelodysplasia and a nonfunctional proximal urethra. The
ly thought to have emotional
detrusor leak-point pressure is high (A). A voiding study is shown from a child with myelodysplasia and a very
low detrusor leak-point pressure (16 cm H2O). Note the nonfunctional internal sphincter (B).
problems; although the lack
of striated sphincter relaxation has been noted by
other workers, it was attributed to volitional factors. Clearly, there is some real
abnormality. In these cases, a bilateral pudendal blockade was transiently associated with involuntary voiding, in some measure confirming the observations of
Fowler et al in such patients.
Neural modulation is effective in treating this condition on an empirical basis thus far.12 This syndrome
emphasizes the critical relationship of the sphincter to
the control of detrusor contractility. The bladder is a
smooth muscle organ under cortical control; it makes
sense that this control is exerted through a striated
Figure 9. Crossed Sling Used to Close a
muscle group innervated by alpha motor neurons conNonfunctional Internal Sphincter and Achieve
nected to the pyramidal tract—a fast system with
Continence
direct cortical connections.
VOLITIONAL SPHINCTER FUNCTION
Onuf ’s nucleus in the anterior sacral horn is a
collection of unique motor neurons that supply the
striated urethral sphincter. Generally, the urethral
sphincter, anal sphincter, and levator muscles work
together, but the neurons in Onuf ’s nucleus specifically innervate the striated urethral sphincter.
Activity of this area is associated with sphincter tone,
contractility, and continence. Inhibition of the
detrusor motor neurons is associated with activity of
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the volitional sphincter. Relaxation of the external
are less well established. Pelvic floor exercises, howevsphincter is the first event in a reflex bladder coner, do have a beneficial effect, and many women so
traction and seems to be required to free the detrutreated feel further treatment with surgery is unnecessor motor neurons from inhibition.
sary. One of the problems here is to determine which
Horseradish peroxidase neural tracing studies, later
patients may benefit from muscle reeducation and
supplemented by rabies viral tracing, demonstrated
strengthening. DeLancey et al concluded that their
the anatomical relationship between the striated
technique of precontraction of the striated sphincter
sphincter and Onuf ’s nucleus.13 The striated sphincter
as a method to stop stress leakage was not effective
and the detrusor motor neurons have a reciprocal relain patients with no levator muscle function.3 An
individual with a nonfunctional proximal sphincter
tionship.14 Striated sphincter activity is associated with
detrusor motor neuron inhibition. Voluntary interrupwould most likely receive no benefit from pelvic
tion of detrusor contraction in progress is associated
floor muscle reeducation, but data by specific type of
with a contraction of the striated sphincter and, withstress incontinence does not exist.
in 1 to 2 seconds, cessation of the contraction. This
Most clinicians who treat incontinence think
relationship underpins one of the effects of sacral neupelvic floor exercises are unsuccessful in patients
ral stimulation in the modulation of uninhibited
with severe intrinsic sphincter deficiency (ISD). The
detrusor reflex activity. By the variation of stimulus
definition of ISD, however, is problematic.
parameters, a sphincteric relaxation can be induced—
Gynecologists generally define ISD in terms of a low
with resumption of detrusor contractility.
urethral pressure, and urologists define ISD by video
Even suprasacral spinal cord injury, which separates
studies showing an open proximal sphincter or a
the sacral cord centers from the brain-stem micturition
very low abdominal leak-point pressure. These are
center, does not destroy the reciprocal relationship
clearly different conditions. A patient with a very
between the bladder and the striated sphincter. Both
low urethral closing pressure related to a very weak
bladder and sphincteric responses are poorly phased
striated sphincter may not respond to pelvic floor
and the normal sequence of events in bladder
filling and contractility is lost, but the basic
relationship is maintained. After suprasacral
spinal cord injury, there is a poor reflex striated sphincter response to bladder filling (the
guarding reflex), but the detrusor response,
when it occurs, is immediately associated
Figure 10. An 11-Year-Old Girl With Severe Stress Incontinence
with a sphincteric contractile response, in the
Associated With an Open Bladder Neck
face of which the detrusor response fades.
Sphincter relaxation occurs as the bladder
contraction stops. Another detrusor contraction occurs with a sphincteric response, and
so on. This can generate high pressures and
can be dangerous, but the basic relationship is
the same.
In addition to control of the detrusor
reflex, the striated sphincter is thought to be
weakened in patients with stress incontinence.
Pelvic floor exercises and direct electrical stimulation have been used to stimulate and
strengthen the striated sphincter.15 Electrical
stimulation was found to have an inhibitory
A
B
effect on reflex detrusor contractility, which is
easy to understand in retrospect. The effects of
The patient is shown before (A) and after (B) a crossed sling procedure. She is continent
but requires intermittent catheterization.
electrical stimulation on stress incontinence
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exercises or to electrical stimulation, and perhaps
neither would a patient with a nonfunctional internal sphincter. Nevertheless, these are not identical
conditions.
MEDICATION FOR STRESS INCONTINENCE
No medications have been approved by the US
Food and Drug Administration for the treatment of
stress incontinence. Alpha receptor agonists, tricyclic
antidepressants, and estrogen have all been used to
treat the condition. Alpha receptor agonists do
increase urethral closing pressure in the proximal urethra experimentally and clinically. Anecdotal reports
have shown successful treatment of stress incontinence
with these agents. Adverse effects are troublesome, and
include hypertension, palpitations, tachycardia, dry
mouth, anxiety, and tachyphylaxis. Thus, these agents
should not be used in elderly patients—the patients in
whom the agents were most often used.
There are also anecdotal reports of estrogen for the
treatment stress incontinence. These agents are effective, but only in patients with long-term estrogen deficiency and a relatively immobile urethra with a very
low leak-point pressure. Estrogen is more effective when
combined with a tricyclic antidepressant. Controlled
double-blind studies of estrogen replacement in postmenopausal women with stress incontinence have not
shown any beneficial effect. This finding is expected
because most kinds of stress incontinence would not
likely respond to estrogen replacement.
Tricyclic antidepressants, such as imipramine, have
direct inhibitory smooth muscle effects in vitro; in
vivo, imipramine has weak anticholinergic effects. The
agent positively affects poor bladder compliance and
can be effective in enuretic children. Imipramine is
also known to prolong norepinephrine reuptake centrally and peripherally. Norepinephrine release in the
pelvic ganglia increases the pelvic nerve preganglionic
activity required to effect a postganglionic contraction,
and thus, proximal urethral relaxation and a detrusor
contraction. Imipramine then seems to delay ganglionic transmission.
Imipramine, alone or in combination with estrogen, has been used to treat stress incontinence and is
occasionally effective for that indication. No studies
conclusively show the agent’s effect on stress incontinence, and there have been no controlled studies
of its efficacy. To treat detrusor hyperactivity,
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imipramine can be used in combination with standard anticholinergic agents with which it has an
additive and perhaps synergistic effect. This is especially easy to determine in patients with spinal cord
injuries who are maintained on intermittent
catheterization protocols and develop reflex detrusor
contractility and incontinence while taking medication, such as extended-release oxybutynin chloride,
30 mg daily. The addition of imipramine usually
resolves the incontinence; however, even if the
incontinence is not resolved, there is a measurable
effect on bladder capacity.
NEW PHARMACEUTICAL AGENTS
Duloxetine, a new antidepressant, has demonstrable in vivo effects on Onuf ’s nucleus. The agent
increases motor neural activity in the nucleus, which
in turn drives contractility of the striated urethral
sphincter (see Figure 1 from Dr Thor’s article, page
678). This effect is due to prolonged reuptake of
norepinephrine and serotonin in the nucleus.16 This
agent would then be expected to facilitate bladder
storage and strengthen the urethral mechanism,
which resists abdominal pressure as an expulsive
force. The effects on bladder storage activity have
been demonstrated experimentally, but not yet clinically (Figure 11).16 Duloxetine is potentially a very
useful agent that will likely have effects on the pelvic
ganglia that are similar to the effects seen in Onuf ’s
nucleus. If so, beneficial effects on urethral function
in both the proximal and striated sphincter areas, as
well as modulation of detrusor reflex contractility
thresholds, would be expected.
Norton et al used duloxetine in a clinical study of
553 women with stress incontinence.17 Some of
these women had symptoms of urge incontinence,
but stress incontinence was the primary problem.
None of the women had previous surgery and all had
a positive cough stress test. The outcome was determined by reduction in incontinence episodes compared with placebo and by quality-of-life testing.
The study compared 3 dose levels (20 mg, 40 mg,
and 80 mg daily) with placebo. The group taking
80 mg daily had a significant improvement in
quality of life and a 64% median reduction in incontinence episodes (Figure 12). Side effects were minimal,
and were similar to those associated with other
selective serotonin reuptake inhibitors and selective
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PROCEEDINGS
Figure 11. Urodynamic Study of the Effect of
Duloxetine on Striated Sphincter Activity
norepinephrine reuptake inhibitors. Nausea was the
most common side effect.
This study included a large group of patients and was
performed with proper selection and a control group.
The results are impressive, but it is difficult to determine
how may patients were completely dry during the study.
Nevertheless, this is the first controlled trial of an agent
to treat stress incontinence. Duloxetine will likely be useful for both stress and urge incontinence, alone or in
combination with other agents.
REFERENCES
There is a dramatic increase in electromyographic (EMG) activity and a
delay in detrusor contractile activity associated with the EMG response.
Reprinted with permission from Thor et al.17
Figure 12. Outcomes of a Phase II Clinical Trial With
Duloxetine in a Large Population of Patients With
Stress Incontinence*
*Pooled diary analysis.
Data from Norton et al.17
688
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