**Abstract:**  
  
Percutaneous tibial nerve stimulation (PTNS) therapy is a minimally invasive
neuromodulation treatment designed to provide sacral nerve stimulation through
percutaneous electrical stimulation of the posterior tibial nerve. Sacral
neuromodulation involves stimulation of the sacral nerve plexus which
regulates bladder and pelvic floor function. In July 2005, the Urgent PC
Neuromodulation System (Uroplasty, Inc.) received 510(k) marketing clearance
for percutaneous tibial nerve stimulation to treat patients suffering from
urinary urgency, urinary frequency, and urge incontinence. This device was
cleared as a class II "nonimplanted, peripheral nerve stimulator for pelvic
floor dysfunction" because it was considered to be substantially equivalent to
the previously cleared percutaneous Stoller afferent nerve system (PerQ SANS
System) in 2001 (K992069, UroSurge, Inc.).  
  
In sacral root neuromodulation, an implantable pulse generator that delivers
controlled electrical impulses is attached to wire leads that connect to the
sacral nerves, most commonly the S3 nerve root that modulates the neural
pathways controlling bladder function. Posterior tibial nerve stimulation
(PTNS) is a technique of electrical neuromodulation proposed for the treatment
of voiding dysfunction including urinary frequency, urgency, incontinence, and
nonobstructive retention in patients who have failed behavioral and/or
pharmacologic therapies. Stimulating the posterior tibial nerve with PTNS is
purported to improve voiding function and control. While the posterior tibial
nerve is located near the ankle, it is derived from the lumbarsacral nerves
(L4-S3), which control the bladder detrusor and perineal floor.  
  
The procedure for PTNS consists of the insertion of a needle above the medial
malleolus near the posterior tibial nerve followed by the application of low
voltage (10mA, 1-10 Hz frequency) electrical stimulation that produces sensory
and motor responses (i.e., a tickling sensation and flexion of the big toe
and/or fanning of all the toes). Noninvasive PTNS has also been delivered with
surface electrodes. PTNS studies have reported 30-minute sessions given weekly
for 4-12 weeks. The usual schedule is one 30-minute session once per week for
twelve weeks. Consideration has been given to increasing the frequency of
treatments to 3 times per week to speed achievement of desired outcomes.  
  
**Rationale/Review of Literature**  
  
In the WellPoint Medical Policy - Treatments for Urinary Incontinence and
Urinary Retention (SURG.00010) published 02/25/2010, a review of literature
related to the Percutaneous Tibial Nerve Stimulation (Urgent PC
Neuromodulation System) documented the following conclusions:

  * The technology of peripheral neuromodulation is still in the relatively early stages of development. Most research in the field has been reported in the last few years with little long-term data available. The bulk of the published studies have been uncontrolled case series. A wide variety of patient populations have been studied, and the inclusion and exclusion criteria used have been variable, as have been both the metrics used to measure responses and the parameters to establish success. Published studies have reported wide variation in degrees of success. The need exists for more randomized, controlled trials as well as data on longer term outcomes. (Cooperberg, 2005).   
  

  * Small case series have reported on an array of conditions with varying results. There is disparity in the treatment length ranging from 8 to 12 weeks and follow-up continues to be short-term. Several studies have shown that any improvement resulting from PTNS is short-lived and there appears to be the need for chronic, maintenance treatment to maintain results (Nuhoglu, 2006; Van Der Pal, 2006). Van Balken (2004) reported that although PTNS is minimally invasive, easily applicable and well tolerated, more data are needed especially on objective parameters and long-term follow-up. In addition, the underlying neurophysiological mechanisms of PTNS need to be studied. Vandoninck (2003) states that PTNS requires further research to determine optimal stimulation parameters and to analyze predictive factors.   
  

  * Since most drug or device studies investigating voiding dysfunction have a large placebo effect, Peters et al (2009a) identified a scientific and clinical need to test PTNS in a controlled clinical trial against a realistic sham treatment and conducted a randomized, blinded control study testing a proposed realistic sham against PTNS on 30 healthy subjects. The participants were blinded when given PTNS stimulation and TENS stimulation (sham). The TENS stimulation was modified to mimic PTNS. In total, 10/30 (33%) of the shams were identified correctly. From this study the authors concluded that subjects are unable to identify whether they are receiving a sham or the PTNS and that this protocol provides a reasonable sham for PTNS controlled studies.   
  

  * Peters et al (2009b) a conducted an industry supported, unblended, randomized trial comparing PTNS and extended-release tolterodine (Detrol LA) in women with overactive bladder syndrome. Subjects had to have symptoms of overactive bladder (OAB) with at least 8 voids per 24 hours; the mean daily voids for those entering the study was 12.3. The primary outcome was the non-inferiority of PTNS in the mean reduction in the number of voids per 24 hours after 12 weeks of treatment. Study findings showed non-inferiority of PTNS based on results for 84 patients. The decrease in voids per day was 2.4 in the PTNS group and 2.5 in the tolterodine group. There was a statistically significant difference in the proportion of patients reporting improvement or cure in symptoms (79.5 vs. 54.8%). Limitations of this study include the lack of blinding to patients and providers as well as lack of a sham/placebo group both to mitigate the potential bias due to subjective outcomes and to evaluate whether either treatment is better than placebo. Another limitation is that it reports on short-term efficacy only.

In addition to the Wellpoint analysis, National Government Services has
reviewed the following published studies (MacDiarmid et al, 2010: Peters et
al, 2010; Finazzi-Agro et al, 2010).

  * MacDiarmid et al (2010) assessed the sustained therapeutic efficacy of percutaneous tibial nerve stimulation in subjects responding to PTNS after 12 weeks of therapy. These "responders" were identified in the Overactive Bladder Innovative Therapy Trial (OrBIT) which compared the effectiveness of PTNS and extended-release tolterodine during 12 weeks of therapy for frequency, nocturia, urgency, voided volume and urge incontinence episodes. A total of 33 PTNS responders continued therapy for an additional nine months. Treatment intervals were selected by the subjects under the supervision of the investigator to allow them to control their symptoms. Subjects received a mean of 12.1 +/- 4.9 treatments during an average of 263 days. Mean number of days between treatments was 21 from the 12-week visit through the 12-month visit. Thirty-two subjects completed 6 months and 25 completed 12 months of therapy. Twelve week results were sustained, but the only measure showing further statistically significant mean improvement at 12 months was the number of moderate-to-severe urgency episodes with values of 3.7 +/- 2.6 at 12 weeks and 2.7 +/- 2.3 at 12 months. However, the p value of 65 years of age. Males were vastly under-represented. Only 25 patients completed the 12 months.   
  

  * The Study of Urgent PC vs Sham Effectiveness in Treatment of Overactive Bladder Symptoms (SUmiT) study by Peters et al (2010) was a multicenter, double-blind, randomized, controlled trial comparing the efficacy of PTNS to sham through 12 weeks of therapy. Two hundred twenty patients with overactive bladder symptoms were enrolled at 23 centers and randomized 1:1 to 12 weeks of weekly percutaneous tibial nerve stimulation (PTNS) or sham treatment. The primary endpoint was to assess the efficacy of PTNS compared to an inactive sham intervention in subjects with overall OAB symptoms in an "intent to treat" analysis. A responder was defined as someone who reported bladder symptoms as moderately or markedly improved on a 7-level global response assessment (GRA) at week 13 after completing 12 treatment weeks. There were 86 (78.2%) females in the PTNS arm and 88 (80.0%) in the sham group. Sixty (54.5%) of the PTNS subjects and 23 (20.9%) of the sham subjects reported moderate or markedly improved overall bladder symptoms from baseline. The p value was 65 years of age were not separately reported; few men in the study; and the need for correct recall for 4 weeks by study participants reporting on the OAB-q short form to obtain at least a portion of the data. Although statistically significant improvements were described for frequency and nighttime void means, the actual ranges overlapped. For example, frequency before and after PTNS treatment was 9.1 - 15.5 and 7 -12.6; with sham values of 9.4 - 15.4 to 7.9 - 14.1. Nighttime voids before and after treatment were 1.3 - 4.5 to 0.2 - 3.5 for PTNS and 1.2 - 4.6 and 1 - 4.2 for sham. Thus, the question of clinical significance versus statistical significance is raised.  
  

  * Finazzi-Agro et al (2010) conducted a prospective, double-blind, placebo controlled study, based on an original placebo technique, performed to evaluate the efficacy of percutaneous tibial nerve stimulation in female patients with detrusor overactivity incontinence. Thirty-five female patients presenting with detrusor overactivity incontinence that had not responded to antimuscarinic therapy were randomly assigned to PTNS or a control group. The percutaneous tibial nerve stimulation group (18 patients) was treated with 12 percutaneous tibial nerve stimulation sessions. The control group (17 patients) received an original placebo treatment. Sessions lasted 30 minutes and were performed three times a week. All patients were evaluated with three-day bladder diaries as well as quality of life scores at baseline and after treatment. The primary outcome measure of this study was the percent of responders in each group, defined as patients with a reduction of 50% or more in urge incontinence episodes. Of 17 patients in the PTNS group 12 (71%) and zero (0) of 15 in placebo group were considered responders (p <0.001). Improvement in the number of incontinence episodes, number of voids, voided volume and incontinence quality of life score were statistically significant in the percutaneous tibial nerve stimulation group but not in the placebo group. Sixty percent of study participants correctly identified whether they were in the PTNS or placebo group. Other study limitations/concerns were the applicability of this study to Medicare beneficiaries > 65 years as the mean age of the PTNS patients was 44.9 and 45.5 years for the placebo group; the small number of study participants; and the electrical current for the placebo was only for a 30 seconds compared to the longer duration for the PTNS patients. The method of treatment blinding for the patients was not described and although the analyzing physician and the statistician were blinded to group assignments, the treating practitioners were not reported to be blinded to patient assignment. In addition, data from only one baseline and one three-day voiding diary were used to determine effectiveness. The timing of the latter was not listed.

Leong et al. (2011) abstracted the records of 141 patients with OAB who had
failed anticholinergic medications and were then treated with PTNS from 2000 -
2009 in a university urogynecology practice to determine PTNS efficacy. A
secondary outcome was to determine the time to response of urinary urgency,
frequency, nocturia, and urge incontinence. All patients had been treated with
at least one anticholinergic medication for a month. If the patient did not
object, a new prescription for an anticholinergic for another month was given
to assure that an adequate trial had occurred. Most patients had a history of
multiple medication trials as well as behavioral modifications. Patients were
told to expect results over weeks rather than overnight. Ten to 12 weeks of
PTNS treatment followed by a tapering schedule developed for the individual
patient occurred and ranged from monthly to three months. A questionnaire
regarding symptoms was verbally given each week.  
  
The mean patient age was 60.4 years with a range from 18- 89. The number of
patients  65 years and their results were not separately reported. All were
female. Using intention to treat, 95 (67.4%) of the patients were satisfied
with their subjective improvement. Of the 116/141 (82.3%) of the patients who
completed treatment, 92/116 (79.3%) were satisfied with their level of
improvement and 90 (77.5%) elected to continue with long-term treatment (4
-103 months). The median week to improvement was five (5) weeks for nocturia,
seven (7)weeks for frequency, six (6) weeks for urgency, and six (6) weeks for
urge incontinence.  
  
Strengths of the study were considered to be the large number of patients from
a single practice in a "real world" setting where patients were not
compensated for their time and encouraged to remain compliant other than would
occur a with the normal standard of care. Weaknesses included the
retrospective design, lack of uniform diagnostic testing and tapering
treatment intervals, and lack of a control group. There were no data beyond
the first 12 weeks of treatment. Analysis of the data for longevity of
effective treatment is planned.  
  
An Agency for Healthcare Research and Quality (AHRQ) report on nonsurgical
treatments for urinary incontinence in adult women was published in April 2012
(Shamliqan et al, 2012). The Executive Summary states, "Percutaneous tibial
nerve stimulation improved UI. Individual RCTs indicated no difference in
adverse effects and treatment discontinuation with active or sham
stimulation." Table B, page ES-24 stated percutaneous electrical stimulation
versus no active treatment had a "Moderate" level of evidence for improved
urinary incontinence (UI) based on three (3) studies (not referenced).
Relative risk was 1.9 with confidence intervals (CIs) (95%) of 1.1 - 3.2 and
absolute risk was 0.31 with CIs of -0.01 -0.18. The number needed to treat was
three (3) with 95% CIs of 2 - 25\. The AHRQ "moderate" level of evidence is
described as follows:

Moderate confidence that the evidence reflects the true effect. Further
research may change our confidence in the estimate of effect and may change
the estimate.

The "Results" portion of the AHRQ report contained Key Question 3, "How
effective is the nonpharmacolgical treatment of UI?" "Clinical Effects of
Percutaneous Nerve Stimulation" (PTNS), page 101 stated it had been shown to
improve urinary incontinence (UI) in adults with OAB and listed four
randomized clinical trials (RCTs). For "Continence," the AHRQ report1 noted,
"No RCTs compared continence after percutaneous tibial nerve stimulation
versus sham stimulation in adults with UI." Not described above is Surwit et
al. (2009) that added PTNS to treatment of 256 patients with urge or mixed
(urge and stress) incontinence. If the latter, urge incontinence needed to be
the more significant problem. Sequential treatments on the same day included
both pelvic floor muscle rehabilitation (PRMR) with biofeedback, pelvic floor
muscle training (PFMT) with exercise and electrical stimulation followed by
insertion of a vaginal probe with electrical stimulation, and then PTNS for 30
minutes. Vaginal estrogen cream or pomegranate oil was used and constipation
and dietary modification also occurred. A totally dry status was reported in
98% of the patients three months after treatment. Eight patients relapsed and
were "re-educated" with dryness being achieved. The author stated, "A
randomized trial of combining biofeedback, PFMT with pelvic exercises, and
electrical stimulation (pudendal and hypogastric nerve neuromodulation) will
have to be done to confirm these results." The AHRQ Evidence-based Practice
Centers (EPCs) prepare reports that are used by a variety of decision makers,
but do not develop recommendations.  
  
An American Urological Association (AUA) Guideline, "Diagnosis and Treatment
of Overactive Bladder (Non-Neurogenic) in Adults: AUA/SUFU Guideline" was
published 2012. The following was included:

18\. Clinicians may offer peripheral tibial nerve stimulation (PTNS) as third-
line treatment in a carefully selected patient population.

_Option (Evidence Strength Grade C)_ "Options" were described as "non-
directive statements that leave the decision to take an action up to the
individual clinician and patient because the balance between benefits and
risks/burdens appears relatively equal or unclear." Evidence level C is
described as "low."  
  
Peters et al. (2012) published the results of an observational study of PTNS
treated patients with overactive bladder syndrome who were considered
responders one week after 12 weeks of treatment in the SUmiT trial. Sixty of
the 103 (58%) out of 110 (55%) individuals receiving active PTNS treatment
considered themselves to be moderately or markedly improved on the 7-level
Global Response Assessment (GRA). Fifty consented to enroll in the STEP study.
Only 35 completed the 24-month study with 34 evaluable questionnaires and 33
evaluable voiding diaries. Therefore, 35/110 or 32% of the initial group and
35/60 or 58% of the enrolled group completed the study. Those enrolled
received a tapering protocol of PTNS of five treatments over 14 weeks and then
in consultation with the investigator began a Personal Treatment Plan for the
remainder of the study. Subjects received a PTNS treatment as OAB symptoms
were increasing and knew that the PTNS treatments were available at any time.
Three-day voiding diaries were completed at completion of the SUmiT trial,
three months post-entry into and every six months thereafter in the STEP.  
  
A mean of 1.3 + 0.7 with a median of 1.2 (range 0.3 - 4.3) treatments per
month were received. The decrease in frequency (12.0 to 9.8) and nighttime
voids (2.7 to 1.8) as well as urinary urge episodes (3.7 to 0.3) and moderate
to severe urgency (8.5 to 2.8) were maintained. [Thirty-eight of the 50
enrollees (75%) had urge urinary incontinence and 73% completed the study.]
Wide ranges were visible on the graphic displays except for the urinary urge
incontinence episodes.  
  
Peters et al. (2013) also published three-year results of patients enrolled in
the STEP study described above. Twenty-nine patients completed the study which
is 26% of the patients receiving the initial active treatment or 48%
considered to have responded to the active treatment. The GRA was used as the
primary efficacy endpoint measure in the initial SUmiT and the two- and three-
year STEP studies. It relies on patient self-report, and relative to subject
assessment tools such as a voiding diary, is a weak measure. In addition,
there were no baseline GRA measures noted for patients in the initial SUmiT,
which is especially concerning because the GRA results rely on patient memory
and thus prevented assessment of improvement in the treatment groups relative
to baseline.  
  
There was no inclusion of the SUmiT trial patients who had responded to sham
nor were there any sham treatments included in this STEP studies. There was
also no notation that behavioral counseling regarding fluid intake or other
measures occurred. The authors concluded "sustained safety and efficacy of
PTNS" occurred with the maintenance regimen.  
  
A Blue Cross Blue Shield Association Technology Assessment, "Percutaneous
Tibial Nerve Stimulation for the Treatment of Voiding Dysfunction" was
published in January 2014. Studies were reviewed for initial treatment and the
maintenance phase. For the initial treatment, two sham-controlled trials were
included. Peters et al. (2010) , the SUmiT trial, was rated as "Good" using
the U.S. Preventative Services Task Force quality of evidence levels. The
trial by Finazzi-Agro et al. (2010) was rated as "Fair." Four comparator
trials were also included in the assessment. Each was graded as "Poor"
regarding the level of evidence. It was concluded that PTNS as a treatment for
voiding dysfunction met the Technology Evaluation Center (TEC) criteria.  
  
In May 2014, the American Urological Association (AUA) published updated
guidelines for the diagnosis and treatment of non-neurogenic overactive
bladder in adults [Gormley et al, (2014)]. Although the evidence level was
still considered Grade C (low balance between benefits and risks/burdens
uncertain), PTNS was upgraded to a "Recommendation" for carefully selected
patients as a third-line treatment of overactive bladder with or without urge
incontinence.  
  
 **Indications and Limitations:**  
  
National Government Services (NGS) will allow PTNS coverage for beneficiaries
with overactive bladder syndrome (OBS) as a less invasive "third-line
treatment" for selected patients who meet the criteria outlined in the AUA's
Guideline as listed below.  
  
PTNS is considered reasonable and necessary for a beneficiary when the
following criteria are met:

  * An evaluation by an appropriate specialist, usually a urologist or urogynecologist, has been performed and the specialist has determined that the patient is a candidate for PTNS; and
  * The medical record documents that the beneficiary has a) been compliant with and failed a trial of symptom-appropriate behavioral therapy of sufficient length to evaluate potential efficacy and b) been compliant with and has failed or been unable to tolerate a trial of at least two appropriate medications administered for four (4) to eight (8) weeks; and
  * The voiding diary shows continued findings of OBS; and
  * The beneficiary has documented a willingness to attend in-office treatment sessions, to comply with the behavioral therapies, and to continue to keep voiding diaries including documentation of behavioral therapy compliance; and
  * Treatment will consist of an initial course of one 30-minute session per week for 12 weeks.

Treatments for relapse shall only be allowed for those patients who achieve a
>50% decrease in OBS symptoms with the initial treatment and then relapse.