SGS Papers

ajog.org

Sacral nerve stimulation reduces elevated

urinary nerve growth factor levels in women
with symptomatic detrusor overactivity
Dara Faye Shalom, MD; Nirmala Pillalamarri, MD; Xiangying Xue, MD; Nina Kohn, MBA, MA;
Lawrence Russell Lind, MD; Harvey Allen Winkler, MD; Christine Noel Metz, PhD
OBJECTIVES: To investigate changes in urinary nerve growth factor
(uNGF) in women with symptomatic detrusor overactivity (DO) following
peripheral nerve evaluation (PNE) for sacral neuromodulation vs
controls.
STUDY DESIGN: There were 23 subjects with overactive bladder

symptoms and DO who failed management with anticholinergics and

22 controls consented to participate in this prospective pilot study.
Urine specimens were collected from controls at baseline for evaluation of uNGF and creatinine. Subjects were evaluated at baseline and
5 days after a trial of sacral nerve stimulation referred to as a PNE.
Each visit included urine collection for uNGF and, Incontinence Quality
of Life Questionnaire, Urinary Distress Inventory Questionnaire, postvoid residual volume, and a 3-day voiding diary. uNGF levels were
measured by enzyme-linked immunosorbent assay and expressed as
uNGF pg/creatinine mg.
RESULTS: Subjects with DO had significantly higher baseline
uNGF levels (corrected for creatinine) compared with controls

(19.82 pg/mg vs 7.88 pg/mg, P < .002). Seventeen DO subjects

underwent PNE and were evaluated at the end of the testing period.
There was a significant improvement in quality of life scores for
subjects after PNE compared with baseline (Urinary Distress Inventory Questionnaire: 7.0 vs 13.7, P < .001; Incontinence Quality
of Life Questionnaire: 87.3 vs 52.8, P < .0001). Concordantly,
uNGF levels significantly decreased from 17.23 pg/mg to 9.24 pg/mg
(P < .02) after PNE.
CONCLUSION: uNGF levels decrease with symptomatic response in DO

subjects undergoing PNE. DO subjects had significantly higher uNGF at

baseline vs controls, and uNGF levels significantly decreased after only
5 days of sacral nerve stimulation. These findings support a larger
study to validate the use of uNGF as an objective tool to assess
therapeutic outcome in patients undergoing PNE for sacral
neuromodulation.
Key words: detrusor overactivity (DO), overactive bladder (OAB),
sacral neuromodulation, urinary nerve growth factor (uNGF)

Cite this article as: Shalom DF, Pillalamarri N, Xue X, et al. Sacral nerve stimulation reduces elevated urinary nerve growth factor levels in women with symptomatic
detrusor overactivity. Am J Obstet Gynecol 2014;211:561.e1-5.

veractive bladder (OAB) is a condition often characterized by

disabling symptoms of urinary urgency
and frequency with or without urge incontinence. Detrusor overactivity (DO)
can be a cause of OAB and is diagnosed
when involuntary detrusor contractions
are noted during the lling phase of
urodynamic testing. OAB is common,

with an estimated prevalence of 16% in

women in the United States, and is
known to adversely affect quality of
life.1,2 Treatment options for patients
with OAB have expanded throughout
the past decade. In patients who are refractory to rst-line treatment with
behavioral modications and anticholinergics, sacral neuromodulation can

From the Division of Female Pelvic Medicine and Reconstructive Surgery, Department of Obstetrics
and Gynecology (Drs Shalom, Pillalamarri, Lind, and Winkler), North ShoreeLong Island Jewish
Health System, Great Neck, and the Center for Immunology and Inammation, The Feinstein Institute
for Medical Research (Drs Xue and Metz), and Biostatistics Unit, Feinstein Institute for Medical
Research (Ms Kohn and Dr Metz), Manhasset, NY.
Received March 10, 2014; revised June 6, 2014; accepted June 23, 2014.
L.R.L. is a consultant for Boston Scientic. The remaining authors report no conict of interest.
This research was supported by a grant from Medtronic Inc, Minneapolis, MN (D.F.S.).
Presented in oral format at the 40th Annual Scientic Meeting of the Society of Gynecologic
Surgeons, Scottsdale, AZ, March 23-26, 2014.
Corresponding author: Nirmala Pillalamarri, MD. npillalama@nshs.edu
0002-9378/$36.00  2014 Elsevier Inc. All rights reserved.  http://dx.doi.org/10.1016/j.ajog.2014.07.007

be offered. This therapy is unique in that

a trial phase, referred to as a peripheral
nerve evaluation (PNE), is performed in
order to determine whether patients
will respond to therapy. During PNE,
patients receive 3-5 days of sacral nerve
stimulation via a temporary test stimulation lead placed in the S3 foramina.
The decision to proceed with permanent implantation of the sacral neuromodulation device, the implantable
pulse generator, is based primarily on
voiding diary results. A patient meets
criteria for implantation if they experience a 50% decrease in the number of
voids and/or leakage episodes during
the testing phase.
Nerve growth factor (NGF) is a small
secreted protein that promotes differentiation and survival of target neurons.
NGF is produced in the bladder and
is reported to sensitize afferent nerves
and induce bladder overactivity.3 This

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bladder overactivity is linked to mechanical stretch and reex bladder
muscle activity.3 NGF has been identied in the bladder urothelium, bladder
smooth muscle, and urine of patients
with OAB.3-5 Recent studies have demonstrated that levels of urinary NGF
(uNGF) correlate with patient reported
bladder symptoms3-6 and may decrease
following successful treatment.3,4,6,7
The cause of OAB remains unclear,
and currently disease severity and response to treatment is assessed through
patient report. The lack of a standardized
noninvasive objective test to evaluate
disease progression and response to
treatment makes the evaluation of patients with OAB exceedingly difcult. It
has been established that NGF is elevated
in the urine of patients with OAB and
DO, and has been shown to decrease
in patients who have a symptomatic
response to therapy.3-7 We aim to conrm this nding in our patient population and to investigate the use of NGF as
a potential biomarker for evaluating
symptomatic response in patients undergoing PNE for sacral neuromodulation. Our hypothesis is that OAB
patients with DO will have elevated NGF
levels as compared with controls and that
the level of NGF will decrease in patients
who have symptomatic improvement
following PNE.

M ATERIALS

AND

M ETHODS

Subjects and study design

This prospective caseecontrol study was
approved by the institutional review
board of the North ShoreeLong Island
Jewish Health System (#11-060A) before
its initiation. This is a pilot study conducted to assess the change in uNGF
levels in DO patients after sacral nerve
stimulation. All subjects (women) gave
written informed consent before study
procedures. Subjects (cases and controls)
were recruited from the urogynecology
practice of the North ShoreeLong Island
Jewish Health System between Aug. 11,
2011, until March 13, 2013. Cases were
enrolled in the study if they had OAB
symptoms including urinary frequency,
urgency or urge incontinence for
greater than 3 months, a urodynamic
diagnosis of DO, and experienced no

ajog.org
improvement following treatment with
anticholinergics and behavioral modications. Controls were age-matched
(5 years), and denied symptoms of
urinary frequency, urgency, or incontinence. Exclusion criteria for both
cases and controls included: presence of
acute cystitis (conrmed by positive
urine culture), urinary tract tumors
or stones, bladder outlet obstruction,
postvoid residual (PVR) volume >100
mL, history of urinary tract operation
(including urogynecologic procedures
such as slings) within 6 months, history
of intravesical botox usage within 1
year, interstitial cystitis, neurologic
disorder, and use of anticholinergics
within the past 21 days.
At baseline, a clean-catch urine specimen was collected from all controls for
determination of uNGF and creatinine
(Cr) levels. All cases completed a 3-day
voiding diary, Incontinence Quality of
Life Questionnaire (I-QOL) and the
Urinary Distress Inventory Questionnaire (UDI-6) at baseline. The I-QOL is a
validated 22-item quality of life instrument specic to urinary incontinence.8
Higher scores indicate a better quality
of life. The UDI-6 is a validated 6-item
questionnaire specic to incontinence
in which higher scores indicate worse
symptoms.9 A clean-catch midstream
urine specimen was collected for determination of uNGF and Cr levels, and a
PVR volume was measured with a
bladder ultrasound. Cases then underwent a 5-day PNE whereby an electrode
(Model 3057 Test Stimulation Lead;
Medtronic Inc, Minneapolis, MN) was
placed into a unilateral S3 foramen under uoroscopic guidance. The technique of the PNE has been described
previously.10 Proper S3 lead placement
was conrmed by uoroscopy as well as
patient sensation of stimulation and
direct observation of plantar exion of
the great toe using the external test
stimulator (InterStim, Medtronic Inc).
The test stimulation lead was then placed
into the test stimulation cable and test
stimulator (Model 3625; Medtronic
Inc). The external handheld test stimulator was adjusted to achieve an optimum level of sensation, and instructions
on using the test stimulator were given.

561.e2 American Journal of Obstetrics & Gynecology NOVEMBER 2014

Cases then began a 5-day trial of sacral

nerve stimulation. A voiding diary was
completed each day of the PNE trial.
After 5 days, cases returned to the ofce
for follow-up and lead removal. The
follow-up visit included collection of a
clean-catch urine specimen followed by
determination of PVR (as described
above), and completion of the I-QOL
and UDI-6.

Urine processing and uNGF and

serum creatinine determinations
Urine samples were centrifuged within
3 hours of collection at 3000 g for 10
minutes. The liquid supernatant was
separated into 1.5 mL aliquots and
stored at 80 C. uNGF (performed in
triplicate) levels were measured using a
specic and highly sensitive enzymelinked immunosorbent assay method
(Emax; Promega, Madison, WI), according to the manufacturers suggestions. Prior studies on uNGF reported
results using the same enzyme-linked
immunosorbent assay kit for reproducibility.11 Sample concentrations were
determined by extrapolating from the
uNGF standard curve. Urinary creatinine levels were determined using the
enzymatic creatinine assay (Diazyme
Laboratories, Poway, CA), according to
the manufacturers directions. Total
uNGF levels (pg/mL) were normalized
by urinary creatinine to overcome differing dilutions of urine between subjects. Data are presented as: mean
(uNGF [pg]/Cr [mg])  SD.
Statistical analyses
Comparisons between groups (cases vs
controls) for uNGF/Cr levels were
made using the ManneWhitney test.
Change in number of leaks and voids
per day, uNGF/Cr levels, and quality of
life measures before and after PNE were
compared in DO subjects using the
Wilcoxon signed-rank test. P values
< .05 were considered signicant.

R ESULTS
Characteristics of the study
population
A total of 23 female subjects with OAB
symptoms and urodynamically proven
DO met inclusion criteria and were

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TABLE 1

Baseline demographics
Factor

Mean (SD) subjects,

n [ 23

Mean (SD) controls,

n [ 22

P value

Age, y

65.3 (17.3)

51.1 (15.2)

.005

BMI (kilograms/meter2)

32.9 (6.9)

26.9 (7.9)

.033

Gravity

2.7 (2.2)

1.3 (1.1)

.106

Parity

2.5 (1.8)

1.3 (1.1)

.106

BMI. body mass index; SD, standard deviation.

Shalom. Sacral nerve stimulation reduces urinary nerve growth factor in detrusor overactivity. Am J Obstet Gynecol
2014.

included in the analyses. Twenty-two female controls were selected and matched
to subjects based on age 5 years. Baseline
demographics are listed in Table 1. The
mean age for subjects was 65.3 years
(range, 24e86 years) and the mean age for
controls was 51.1 years (range, 29e73
years). There was 1 subject who was not
matched for age by a control.
At baseline, subjects with DO had
signicantly higher mean uNGF/Cr levels
compared with controls (19.82 pg/mg 
21 pg/mg vs 7.88 pg/mg 7.7 pg/mg,

P < .002). These ndings are shown in

the Figure.
All DO subjects underwent PNE and
17 completed follow-up after 5 days of
test stimulation. Six subjects did not
complete the testing phase. Of the 6
subjects, 3 had lead displacement and 3
discontinued the test because of discomfort from nerve stimulation. Lead
displacement was diagnosed in patients
who perceived stimulation in areas other
than the vagina, anus, and perineum,
and was conrmed by the clinician who

FIGURE

Baseline uNGF/Cr levels in subjects compared with controls

Cr, creatine; uNGF, urinary nerve growth factor.

Shalom. Sacral nerve stimulation reduces urinary nerve growth factor in detrusor overactivity. Am J Obstet Gynecol 2014.

noted improper location of a lead. All 3

patients with lead displacement reported
accidentally pulling the lead and noticing
a signicant change in sensation. Data
were collected on the 17 remaining
subjects who underwent the complete
5-day testing phase. All subjects had a
>50% decrease in the number of daily
voids and/or leakage episodes following
PNE. Descriptive data for number of
leaks and voids (per 24-hour period) on
day 5 compared with baseline are shown
in Table 2. There was not only a signicant reduction in symptom distress as
measured by the UDI-6 (7.0  5.8 vs
13.7  4.4, P < .001), but also a statistically and clinically signicant rise in
health-related quality of life as determined by the I-QOL (87.3  23.5 vs 52.8
 21.2, P < .0001) for subjects after PNE
compared with baseline. Concordantly,
mean uNGF/Cr levels signicantly decreased from 17.23 pg/mg  20.7 pg/mg
to 9.24 pg/mg  7.1 pg/mg (P < .02)
after PNE. In addition, mean PVR
volume signicantly decreased from
17.9 mL  19.1 ml at baseline to 2.1 mL
 5.9 ml after PNE (P < .002). Results
are presented in Table 3.

C OMMENT
In this pilot study, uNGF levels were
measured in subjects before and after
treatment with sacral neuromodulation.
We demonstrated that uNGF levels
decrease with therapeutic response in
patients with OAB and DO undergoing
PNE. Mean uNGF levels were more than
twice as high in DO subjects at baseline
compared with those observed in normal controls, and uNGF levels signicantly decreased after only 5 days of
sacral nerve stimulation.
Several previous studies report
similar uNGF ndings in DO patients
undergoing alternative therapies. Levels
of uNGF have been shown to decrease
following successful treatment with patients who respond to therapy is unclear.
Giannantoni et al12 reported that botulinum toxin-A reduces NGF levels in
subjects with DO by decreasing acetylcholine release at the presynaptic level
and thus decreasing detrusor contractility and production of NGF. In patients
who respond to anticholinergics, the

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TABLE 2

Number of leaks and voids (per day) 5 days postPNE compared with
baseline
Variable

Lower
Upper
Median Quartile Quartile Minimum Maximum P value

Leaks at baseline 16

3.0

3.0

7.0

1.0

12.0

NS

Leaks day 5

16

1.0

0.0

2.0

0.0

8.0

NS

Change in leaks

16

2.5

4.0

1.0

12.0

1.0

Voids at baseline

17

13.0

10.0

15.0

7.0

29.0

NS

Voids day 5

17

7.0

6.0

8.0

4.0

10.0

NS

Change in voids

17

7.0

9.0

4.0

19.0

0.0

.0003

< .0001

NS, not significant; PNE, peripheral nerve evaluation.

Shalom. Sacral nerve stimulation reduces urinary nerve growth factor in detrusor overactivity. Am J Obstet Gynecol
2014.

authors postulate that the reduction in

uNGF may be associated with suppression of bladder smooth muscle stretching as a consequence of improvement in
DO symptoms.13 Although the precise
mechanism of action of sacral neuromodulation is unknown, it is generally
accepted that it works via the stimulation of afferent rather than efferent
nerve bers.14 The proposed pathway
for the role of NGF in DO is that NGF
sensitizes afferent C-bers leading to
sensory urgency and detrusor overactivity. It has also been suggested that
NGF induces bladder overactivity by
altering the expression of sodium or
potassium channels used by the bladder
afferent bers.15 Therefore, it is plausible that sacral neuromodulation, a
treatment designed to stimulate afferent
nerves in the overactive bladder, would
alter uNGF levels.

The success rate of sacral nerve stimulation is reported to be in the range of 55%
to 80%.14 This success is limited by the fact
that no predictive variables of outcome
have been identied. Currently, the
response to sacral neuromodulation is
predicted based on patient reported
symptoms and voiding diaries during the
PNE trial. In this study, we introduced
uNGF as an additional tool to evaluate
treatment response to PNE. All DO subjects in our study population experienced
symptomatic improvement during the 5day PNE. PVR was found to decrease as
well; however, this is not clinically relevant
as volumes of <50 mL are considered
normal. A reduction in uNGF levels was
observed in conjunction with a decrease in
voiding/leakage frequency, and improvement in quality of life scores. An assessment
tool that combines responses to quality of
life questionnaires, voiding diaries, and

uNGF levels may offer a more reliable

predictive outcome measure for PNE.
To our knowledge, the minimal
amount of time it takes for a detectable
change in uNGF level to occur has
not been determined. During the study
design, questions arose regarding
whether changes in uNGF levels could
be detected after only 5 days, or if
more time would be required. On our
review of the literature, the minimum
time between measurements of uNGF
(before and after treatment) was 30
days, and prior studies assessing a
change in uNGF levels within a shorter
time interval were not found. With this
study, we demonstrated that changes in
uNGF can be detected in as little as 5
days, supporting the concept that clinicians could determine the potential
success of an implanted sacral neuromodulation device for DO patients after a 5-day PNE using uNGF levels, as
well as QOL indices and PVR volumes.
There are several limitations to this
study. Although controls were agematched to subjects 5 years, mean age
was greater amongst subjects compared
with controls. It is possible that age had an
effect on uNGF levels. The fact that all
subjects who completed PNE responded
to treatment prevented us from measuring
changes in uNGF levels in subjects with
unchanged or worsened symptoms. In
other words, it was not possible to determine what effect an absent or negative
response to treatment would have on
uNGF levels. It is plausible that subjects
could have a decrease in uNGF levels after
undergoing unsuccessful PNE.

TABLE 3

uNGF/Cr, PVR, and quality of life questionnaire results 5 days postPNE compared with baseline
Value at baseline

Value 5 days postpone

Mean (SD)

P value

Factor

Median (Q1, Q3)

Mean (SD)

Median (Q1, Q3)

uNGF (pg) /Cr (mg)

13.0 (6.9, 18.2)

17.2 (20.7)

7.1 (4.7, 12.8)

9.2 (7.1)

.0267

PVR (milliliters)

15.0 (0.0, 28.0)

17.9 (19.1)

0.0 (0.0, 0.0)

2.1 (5.9)

.0020

UDI-6

14.0 (12.0, 16.0)

13.7 (4.4)

6.0 (4.0, 10.0)

7.0 (5.8)

.0012

I-QOL

58.0 (33.0, 72.0)

52.8 (21.2)

93.0 (77.0, 105.0)

87.3 (23.5)

< .0001

Cr, creatinine; I-QOL, Incontinence Quality of Life Questionnaire; PNE, peripheral nerve evaluation; PVR, postvoid residual; SD, standard deviation; UDI, Urinary Distress Inventory Questionnaire;
uNGF, urinary nerve growth factor.
Shalom. Sacral Nerve Stimulation reduces urinary nerve growth factor in detrusor overactivity. Am J Obstet Gynecol 2014.

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Another limitation was our use of
PNE as the only testing method for
sacral neuromodulation. Six subjects
did not complete the PNE because of
lead displacement or removal secondary to discomfort. At the time this
study was performed, PNE was the
preferred method of testing for sacral
neuromodulation in our urogynecology practice. This was secondary to the
ability to perform PNE in the ofce
setting as well as patient convenience.
As a result, this was the only method of
testing included in our study. Because
that time we have started to perform
the stage 1 procedure more frequently
as the risk of lead migration is minimal
with implantation of the tined lead.
Our small sample size was an additional limitation. We are currently
conducting a larger study with longterm follow-up to assess the changes
in uNGF levels in DO patients after 12
months of sacral nerve stimulation.
That data should provide additional
information on uNGF variability
within an individual. In addition, we
are investigating the use of uNGF in the
testing phase (PNE) as a predictor of
short- and long-term treatment response to sacral neuromodulation.
Results from this pilot study are
consistent with previous research that has
demonstrated that uNGF is elevated in
patients with OAB/DO and decreases with
symptomatic response to treatment. Over

the past few years evidence has accumulated from both animal and human
studies supporting the use of uNGF as a
potential biomarker for OAB and DO.
Although these results are promising,
questions remain regarding the specicity, sensitivity, and cost-effectiveness of
uNGF as a tool for diagnosis and evaluation of treatment response. Further
investigation is necessary before the
consideration of uNGF as a biomarker for
this condition.
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