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`ELECTRICAL NEUROMODULATORY THERAPY IN FEMALE VOIDING DYSFUNCTION
`BOSCH
`
`Electrical neuromodulatory therapy in female
`voiding dysfunction
`
`J.L.H. RUUD BOSCH
`Department of Urology, University Medical Centre Utrecht, Utrecht, the Netherlands
`
`Female voiding dysfunction such as urge-
`frequency syndrome, urge incontinence and
`unobstructive urinary retention are often
`refractory to conservative management.
`Electrical neuromodulation with surface
`electrodes or with implantable systems has
`become a valuable addition to the therapeutic
`options in the last two decades. Interstitial
`cystitis is an emerging indication. The
`application of these techniques in non-
`neurogenic patients is reviewed. The
`techniques using unimplantable electrodes,
`
`anogenital electrical stimulation with plug
`electrodes, transcutaneous electrical nerve
`stimulation with surface electrodes, and
`posterior tibial nerve stimulation using needle
`electrodes are addressed. Several techniques
`using implantable systems are discussed, e.g.
`TM
`sacral nerve neuromodulation (Interstim
`
`device), pudendal nerve stimulation (Interstim
`TM
` device) and paraurethral
`and Bion
`TM
`neuromodulation (Miniaturo
` device). The
`long-term efficacy of neuromodulation for
`the established indications is more than half,
`
`but 20–50% of the patients initially tested
`do not respond to a test procedure. The
`disadvantage is the high surgical revision rate
`and the high cost of treatment. Technical
`advances will hopefully be able to address
`these aspects.
`
`KEYWORDS
`
`neuromodulation, incontinence, female,
`voiding, neurogenic, stimulator
`
`INTRODUCTION
`
`Female voiding dysfunction such as those
`related to overactive bladder (OAB) syndrome,
`unobstructive urinary retention and
`interstitial cystitis (IC) often are refractory
`to conservative management, including
`drug therapy, behavioural therapy, pelvic
`floor muscle exercises, biofeedback and
`intermittent self-catheterization.
`Neuromodulation and particularly sacral
`neuromodulation (SNM) has proved to be
`valuable in these situations [1]. The currently
`available methods include: anogenital
`electrical stimulation, transcutaneous
`electrical nerve stimulation (TENS), posterior
`tibial nerve stimulation (PTNS), SNM,
`pudendal neuromodulation (PNM) and
`paraurethral neuromodulation.
`
`The precise mode of action of
`neuromodulation is unknown. Its effects can
`be explained by modulation of reflex
`pathways at the spinal cord level [1,2].
`However, there are now studies that indicate
`that supraspinal pathways are also involved
`[3]. Experimental work in animals, human
`volunteers and patients shows that at least
`two mechanisms are important: (i) Activation
`of efferent fibres to the striated urethral
`sphincter reflexively causes detrusor
`relaxation; (ii) Activation of afferent fibres
`causes inhibition at a spinal and/or
`supraspinal level.
`
`Tanagho and Schmidt [4], who introduced
`SNM, adhered to the first theory. In
`agreement with this theory, Shafik [5] showed
`that electrical stimulation of the external
`urethral sphincter in human volunteers
`can inhibit detrusor contraction. Studies
`supporting the second theory are those in
`which the dorsal clitoral or dorsal penile
`nerve, both purely afferent branches of
`the pudendal nerve, were electrically
`stimulated. This induced a strong inhibition
`of the micturition reflex and detrusor
`hyper-reflexia [6–8]. Thus, pudendal nerve
`afferents are particularly important for
`the inhibitory effect on the voiding reflex.
`Pudendal afferent activity mapping during
`neurosurgical procedures of the sacral nerve
`roots has shown that the S1, S2 and S3 roots
`contribute 4%, 60.5% and 35.5%, respectively,
`of the overall pudendal afferent activity
`[9]. Despite that S2 carries more pudendal
`afferents, the S3 spinal nerve is the
`preferential site of lead implantation in
`TM
`conjunction with the Interstim
` device
`(Medtronic, Minneapolis, MN, USA).
`Stimulation of S3 in comparison to S2
`causes less undesired excitation of efferent
`fibres that innervate leg muscles. However,
`it was also shown that pudendal afferent
`distribution is confined to a single level (i.e.
`S2) in 18% of the subjects [9]. A lack of effect
`of S3 stimulation can therefore be expected in
`some subjects and direct pudendal nerve
`stimulation might be more effective.
`
`Experimental work in spinalized rats showed
`that neuromodulation reduced the degree of
`
`c-fos
`hyper-reflexia and the expression of the
`gene after bladder instillation with acetic acid
`[10]. (C-fos protein is expressed in the spinal
`cord after irritation of the lower urinary tract;
`this expression is mainly mediated by afferent
`C fibres). This result shows that inhibition of
`afferent C fibre activity might be one of the
`underlying mechanisms of neuromodulation.
`Patients with IC might benefit from this
`effect.
`
`Paradoxically, neuromodulation also works
`in patients with urinary retention in the
`absence of anatomical obstruction. It was
`postulated that neuromodulation interferes
`with the increased afferent activity arising
`from the urethral sphincter, restoring the
`sensation of bladder fullness and reducing the
`inhibition of the detrusor muscle contraction
`[11].
`
`Detailed assessment of the sensory response
`during lead placement is important for long-
`term success. This is now possible with a two-
`stage procedure using tined lead placement
`under local anaesthesia. In a comparative
`study between the traditional and the first
`et al.
`
`stage of the two-stage implant, Peters
`[12] reported a re-operation rate of 43% vs
`0%, respectively, after a mean follow-up of
`5.6 months. It is clear that the mechanisms of
`action of neuromodulation are still debated,
`
`©
`2 0 0 6 T H E A U T H O R
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`J O U R N A L C O M P I L A T I O N
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`2 0 0 6 B J U I N T E R N A T I O N A L | 9 8 , S U P P L E M E N T 1 , 4 3 – 4 8
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`4 3
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`Petitioner - Avation Medical, Inc.
`Ex. 1039, p. 43
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`

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`B O S C H
`
`but stimulation of afferent pathways seems
`to play a crucial role.
`
`TENS
`
`ANOGENITAL ELECTRICAL STIMULATION
`
`The first publications on anogenital electrical
`stimulation as a treatment option in the OAB
`appeared in the 1970s [2] and the technique
`can now be considered an established
`treatment [13]. The method implies the
`insertion of plugs equipped with electrodes
`into the anal canal and (or) the vagina.
`Two modes of this type of therapy can
`be distinguished. Long-term or chronic
`stimulation implies a home-treatment
`programme for several (e.g. 3–12) months.
`This is mainly used in stress incontinence. In
`acute maximal stimulation the patient is
`treated in a limited number (usually 4–20,
`sometimes much more) of sessions.
`
`It was stated that anogenital
`electrostimulation has a beneficial effect in
`about half of the patients [14,15]. However,
`the reported results vary considerably [16,17].
`Most [18–20] but not all [21] authors found
`that active treatment was superior to sham
`treatment.
`
`Success rates heavily depend on the selection
`of patients. As an example, Primus and
`Kramer [22] obtained a success rate of
`64% in a group of patients with idiopathic
`detrusor instability 2 years after treatment,
`while all patients with multiple sclerosis,
`who initially had benefited, relapsed within
`2 months. Disappointing results were also
`obtained in elderly cognitively impaired
`patients [23].
`
`Geirsson and Fall [13] noted that the results
`obtained with a routine outpatient procedure
`were far less good than those obtained in
`their prospective research series. No data are
`available on the minimum number of
`
`et al. [24] found
`treatments required. Siegel
`no significant difference between daily and
`every-other-day treatment.
`
`Few studies reported success rates after a
`>
`6 months. Of the 17 patients
`follow-up of
`
`et al. [20], 41% remained
`treated by Yamanishi
`cured for 9 months on average after
`stimulation, with no intervention. The success
`
`et al.
`rate of 85% initially obtained by Eriksen
`[16] in 48 idiopathic females fell to 77% after
`1 year. No severe side-effects have been
`reported.
`
`4 4
`
`TENS is used widely in the treatment of pain
`
`et al. [25]
`in various conditions. Fall
`successfully treated patients with IC with
`surface electrodes stuck over the suprapubic
`area. In the treatment of the OAB, the
`electrodes are usually stuck over the S2 and
`S3 dermatomes (peri-anal region) or over the
`sacral foramina S2 and S3. Stimulation takes
`place daily during one or more weeks.
`Beneficial results of TENS at various sites have
`been reported [26].
`
`et al. [27], with
`
`Of patients treated by Walsh
`sacral dermatome TENS, 76% and 60%
`reported an improvement in daytime
`frequency and urgency, respectively, while
`56% noted a reduction in nocturia. Hasan
`>
`
`et al. [28] reported a
`50% decrease in the
`urinary frequency in 37% of 59 patients with
`an unstable bladder. The number of leakages
`>
`improved by
`50% in 69% of those with urge
`incontinence. In a group of 55 children aged
`6–12 years, 57% and 33% of those with
`daytime incontinence and bedwetting,
`respectively, became dry, while the voiding
`frequency became normal in 67% [29]. Hasan
`
`et al. [28] saw no urodynamic improvement
`with TENS over the posterior tibial nerve and
`the suprapubic region.
`
`Application of TENS is not useful if the patient
`is not offered the opportunity for re-
`treatment. The symptoms of all 25 patients
`
`
`who were successfully treated by Walsh et al.
`[27] returned to pretreatment levels within
`6 months. Local skin irritation at the site of
`the electrodes is seen in a third of the patients
`[28].
`
`PTNS
`
`Intuitively, the pelvic region is the most logical
`place to seek a site for neuromodulation, but
`physiological mechanisms permit suppression
`of bladder overactivity from a more distant
`location. In PTNS, a thin acupuncture needle is
`inserted 5 cm cephalad from the medial
`malleolus and just posterior to the margin of
`the tibia at the site of the posterior tibial
`nerve. This is a well-known acupuncture point
`[30]. Treatment usually takes place weekly for
`10–12 weeks. Chang [30] showed statistically
`significant changes in the maximum
`cystometric capacity in a group of 26 women
`immediately after a 30-min treatment
`session; such changes were absent in a
`control group. Despite these promising
`
`results, it took some time before Stoller [31]
`introduced this technique in urological
`TM
`practice (PercSANS
`). In an abstract, he
`described an 81% clinical success rate in 90
`patients after a mean follow-up of 5.1 years.
`More recently, modest results were reported
`[32]. Clinical success, defined as the wish of
`the patient to continue treatment after an
`initial 12-week treatment period, was
`reported in 60% of 30 patients with urge
`incontinence and in seven of 12 with
`retention. In the successfully treated patients
`with retention, none of the voiding variables
`were statistically significantly improved. In
`the patients with urge incontinence the
`percentage of leaking episodes decreased by
`63% in those successfully treated, vs 24% in
`the unsuccessful group [32]. Only minor side-
`effects such as pain or bleeding at the
`puncture site have been reported.
`
`SNM
`
`SNM (Interstim therapy) differs from other
`types of neuromodulation by its continuous
`stimulation and close nerve contact. Its
`characteristic feature is the implantation of a
`pulse generator and an electrode stimulating
`one of the sacral nerves, mostly S3. Patients
`only have a permanent implant if the
`preceding percutaneous nerve evaluation
`(PNE) test is successful, or if the effects of the
`first stage of a two-stage implantation are
`favourable. In the first stage, only an electrode
`is implanted but not the pulse generator.
`Patients in whom the symptoms of the
`voiding dysfunction are reduced by more than
`half during testing can receive the permanent
`implant (Fig. 1).
`
`Established indications for this treatment are
`urge-frequency syndrome, urge incontinence
`and unobstructive urinary retention. IC is an
`emerging indication. It appears that the
`percentage of patients responding to the
`traditional test stimulation (PNE) is 60–70%
`[33]. Recent experience with the staged
`implant using a tined lead has resulted in a
`higher implantation rate of up to 80% in
`patients with various indications [34,35]. It is
`still unclear how the long-term results in this
`additional group of responders compare to
`the long-term results in responders to the
`traditional PNE test.
`
`The results in patients with urge incontinence
`were summarized previously [33].
`Symptomatically, about half of patients
`with urge incontinence and no neurogenic
`
`J O U R N A L C O M P I L A T I O N
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`©
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`2 0 0 6 T H E A U T H O R
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` 2 0 0 6 B J U I N T E R N A T I O N A L
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`Petitioner - Avation Medical, Inc.
`Ex. 1039, p. 44
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`E L E C T R I C A L N E U R O M O D U L A T O R Y T H E R A P Y I N F E M A L E V O I D I N G D Y S F U N C T I O N
`
`FIG. 1. Anteroposterior radiograph of the pelvis with
`
`the Interstim pulse generator in a buttock position
`and with the electrode placed in the S3 sacral
`foramen.
`
`-+-;.
`
`4'1ft
`., . •
`\·
`~ \~
`
`>
`90% improvement in their
`causes have a
`incontinence after the permanent implant;
`25% have a 50–90% and another 25% a
`<
`50% improvement. In two comparative
`multicentre studies involving patients with
`refractory urge incontinence and urgency-
`frequency, respectively, half of the patients in
`whom the PNE test was successful were
`implanted [36,37]. Implantation was delayed
`for 6 months in the remaining patients, who
`received standard medical treatment and
`comprised the control group. The stimulation
`groups had significantly better symptomatic
`results than the control groups at 6 months
`of follow-up.
`
`After the 3-year [38] and 5-year [39] follow-
`up, respectively, sustained good results were
`reported, with a reduction of more than half
`in leaking episodes per day in 53% and 59%
`of the implanted patients, respectively.
`Furthermore, 46% and 22%, respectively,
`were considered dry [38,39]. However, one
`group reported less good results [40]. These
`authors reported on the long-term experience
`(mean follow-up 6.5 years) in a total of 52
`implanted patients, of whom 41 were
`available for evaluation. Of these, six were in
`the urge incontinence group; there was
`persistent improvement in only one of the six.
`It was shown previously that the success rate
`decreases most rapidly in the first 1.5 years
`after implantation of the device [41].
`
`implanted patients with OAB symptoms.
`
`et al. [40] reported persistent
`Elhilali
`improvement in 10 of 22 (45%) patients with
`urge-frequency after a mean follow-up of
`6.5 years.
`
`SNM for treating unobstructive urinary
`retention is another established indication.
`
`et al. [43] reported that 68 of 177
`Jonas
`patients in retention responded to traditional
`>
`PNE with a
`50% improvement. Of the
`implanted patients, 69% eliminated
`catheterization at 6 months of follow-up
`and an additional 14% had a reduction of
`more than half in catheterization volume. At
`18 months of follow-up catheterization was
`completely eliminated in 58% of 24 evaluable
`
`et al. [11] reported a 68%
`patients. Swinn
`success rate to PNE in 38 women, mostly with
`Fowler’s syndrome. The same group reported
`their long-term results in 26 implanted
`women. After a mean follow-up of
`37 months, 17 of 26 (65%) women voided
`spontaneously with no need for self-
`catheterization [44]. After a mean follow-up
`
`et al. [42]
`of 70.5 months, Van Voskuilen
`reported ‘good results’ in 76.2% of implanted
`patients with urinary retention.
`
`Several authors used permanent implants of
`the InterStim device for treating patients with
`IC. Mixed results were reported with SNM of
`S3. Some investigators report good results,
`with up to 75% improvement in symptoms
`[12,45,46], including a 20% ‘cure’ rate [45].
`The follow-up in these studies was relatively
`
`et al. [47]
`short, at 5.6–14 months. Berman
`could not confirm these results; in 13 patients
`who were implanted with the Interstim
`device, only two were pleased or delighted
`
`et al. [40] reported
`with the results. Elhilali
`that of four patients with IC and intractable
`pelvic pain, only one was improved after a
`mean follow-up of 6.5 years.
`
`At present, the only way to determine
`whether a patient is a candidate for
`implantation is a PNE test or a staged
`implantation. Attempts to identify factors
`predicting the success of SNM failed [37,48].
`Psychological factors seem to be important
`[33,49].
`
`et al. [38]
`
`In the urge-frequency group, Siegel
`reported that 2 years after implantation, 56%
`of the patients had a reduction of more
`than half in voiding frequency. After a mean
`
`et al.
`follow-up of 69.8 months, Van Voskuilen
`[42] reported ‘good results’ in 63.6% of 107
`
`The need to reposition the electrode after
`migration is the most frequently reported
`≈
`20% of the
`adverse event, occurring in
`patients [37,41]. Some patients complained of
`pain at the site of the pulse generator, which
`resolved after repositioning. Pain in the leg
`
`©
`2 0 0 6 T H E A U T H O R
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`J O U R N A L C O M P I L A T I O N
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`©
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` 2 0 0 6 B J U I N T E R N A T I O N A L
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`can often be reduced by decreasing the
`et al.
`
`stimulation amplitude. Van Voskuilen
`[42] reported a re-operation rate of 48.3%
`(excluding pulse generator replacements)
`after a mean follow-up of 64.2 months.
`
`et al. [44] reported an overall
`Dasgupta
`adverse-event rate of 51.6%. Siegel et al. [38]
`
`
`reported the adverse events for 219 Interstim-
`implanted patients; the commonest events
`were pain at the stimulator site (15.3%), new
`pain (9%), pain at the lead site (5.4%),
`suspected lead migration (8.4%), infection
`(6.1%), transient electric shock (5.5%) and
`adverse changes in bowel function (3%).
`
`Displacement of the electrode during the PNE
`test might give a falsely negative result.
`
`
`Janknegt et al. [50] therefore repeated the test
`by placing a permanent electrode and an
`extension cable in patients in whom
`displacement was suspected, and connected
`those to an external pulse generator. The
`permanent pulse generator was placed at a
`later stage if the patient had a good response
`(which was so in eight of 10 patients). The
`two-stage implant has now become the
`standard, particularly since the introduction
`of a minimally invasive technique for the
`placing a tined lead [35]. The pulse generator
`was traditionally placed in a lower abdominal
`pocket. Buttock placement has the advantage
`that the patient need not be repositioned
`≈
`during operation, and it saves
`1 h of
`operative time; this has become the standard
`[51].
`
`PNM
`
`Considerably many patients do not respond to
`SNM; this has fuelled the interest in the use of
`PNM. In a single-blind randomized crossover
`trial of SNM vs PNM in a group of 30 patients
`it was recently shown that 80% responded to
`the testing phase and that six had no
`response to either lead. Of the responders,
`79% had chosen the pudendal lead as the
`superior one. In this study the Interstim device
`with tined lead, placed either at the pudendal
`nerve via a posterior approach or the
`traditional placement in the S3 foramen, was
`used [52].
`
`Another approach recently reported is
`implantation of the Bion device (Advanced
`Bionics Corp., Valencia, CA, USA) [53]. This
`rechargeable device is a self-contained,
`battery-powered, telemetrically
`programmable, current-controlled mini-
`neurostimulator with an integrated electrode.
`
`4 5
`
`Petitioner - Avation Medical, Inc.
`Ex. 1039, p. 45
`
`

`

`B O S C H
`
`×
`It is 27
` 3.3 mm and can be implanted
`adjacent to the pudendal nerve.
`
`Subjects qualify for implantation after a
`positive percutaneous screening test (PST). A
`PST is considered positive if stimulation
`results in an increase of more than half in the
`bladder volume at the first involuntary
`detrusor contraction or the maximum
`cystometric capacity. After a successful PST
`the Bion can be implanted at its target
`location, adjacent to the pudendal nerve at
`Alcock’s canal (Fig. 2); it is implanted with a
`specially developed tool kit.
`
`The results obtained with the Bion in a pilot
`study of female patients with refractory
`detrusor overactivity incontinence were
`reported [53]; six of 14 responded to the PST
`and received an implant. After 6 months of
`follow-up the mean number of incontinence
`episodes decreased from 6.2 to 2.4 per day
`[53]. Given that five of six patients had failed
`SNM, this decrease in incontinence episodes is
`encouraging. Clinical trials of the Bion device
`involving more patients are underway.
`
`PARAURETHRAL NEUROMODULATION
`
`The Miniaturo-I system (BioControl Medical
`Ltd., Israel) is a new implantable system for
`the treatment of painful bladder syndrome
`and urinary voiding dysfunction [54].
`It consists of a battery-powered
`electrostimulator and a stimulation lead. The
`stimulation lead is placed paraurethrally in
`the pelvic floor. The location of the electrode
`is comparable to the position described by
`Caldwell [55], who was the first to use chronic
`electrical stimulation for the treatment of
`incontinence, in 1963.
`
`Test stimulation is used to assess the patient’s
`suitability for permanent implantation. The
`Miniaturo Test System consists of an external
`unit and a stimulation lead. Typically, patients
`were asked to wear the test system for 6–48 h
`in the pilot studies and to keep voiding and/or
`pain diaries during that period. Implantation
`can be done under local anaesthesia. The
`electrostimulator is placed in a suprapubic
`subcutaneous ‘pocket’. The stimulation lead is
`directed towards the urethral sphincter via a
`small vaginal incision (Fig. 3).
`
`The feasibility study of the Miniaturo-I in
`patients with IC was planned to determine the
`safety, objective and subjective efficacy of
`electrical stimulation of the paraurethral
`
`4 6
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`pelvic floor for the treatment of this condition
`[56]. The inclusion criteria were formulated to
`reflect the clinically based, definition of IC, i.e.
`the presence of Hunner’s ulcers and petechial
`haemorrhages is not obligatory, and either
`pain or voiding symptoms are inclusion
`criteria.
`
`Of 73 enrolled patients (mean age 55.5 years),
`22% did not pass the test procedure [56]; 57
`were implanted with the Miniaturo-I system.
`Of these patients, 23% withdrew their
`consent to participate in the study, at 1–25
`months after implantation, and mainly due to
`a self-perceived lack of efficacy. Of 57
`patients, 45 completed a mean (range) follow-
`up of 18 (1–40 months) and had a
`considerable improvement in symptoms. The
`mean (
`) urinary frequency moderately
`SD
`improved from 24.4 (15.1) per day at baseline
`to 18.2 (12.2) at a mean follow-up of
`=
`
`18 months (P
`
` 0.02). The pain score on the
`visual analogue scale (range 0–10) improved
`from 6 (1.9) to 3.1 (2.2). The pain score on the
`Short Form-Minnesota Pain Questionnaire
`improved from 36.6 (10.7) to 17.4 (11.2)
`<
`
`
`(P
` 0.001). The O’Leary-Sant IC index
`improved from 31.4 (3.9) to 20.3 (9.7),
`representing an improvement in quality of
`life.
`
`The feasibility study in patients with urgency/
`frequency and urge incontinence was
`initiated in August 2002; the results obtained
`in the first seven patients were reported [54].
`Patients completed a mean follow up of
`14.5 months after implantation. In one
`patient the device had to be explanted
`because of infection after 10 months of
`follow-up. At the last follow-up visit five
`women were completely dry and two reported
`a reduction in the number of leaking episodes
`from 15 to 6.7, and from 12 to 4 per 24 h,
`respectively. The degree of urgency, on a scale
`from 0 (‘no urgency’) to 3 (severe urgency),
`significantly improved from 2.0 at baseline to
`1.4 at the last follow-up.
`
`Of 79 implanted patients, 34 had 77 device-
`or therapy-related adverse events [57];
`29 needed surgical intervention (i.e.
`repositioning or replacement), giving a
`patient surgical revision rate of 36.7%. The
`number of events after implantation that
`required surgical intervention was 46.
`
`The initial results in patients with IC or OAB
`are encouraging. The implantation procedure
`is simple and quick. In patients with IC, there
`
`FIG. 2. Anteroposterior radiograph of the pelvis with
`
`the Bion in position close to Alcock’s canal.
`
`FIG. 3. Anteroposterior radiograph of the pelvis with
`
`the Miniaturo-I pulse generator in a suprapubic
`position and with the electrode situated para-
`urethrally.
`
`>
`70% [56]. The long-
`was an improvement in
`term results of treatment with the Miniaturo-
`I device in patients with IC remains to be
`determined. The preliminary and relatively
`small experience with the Miniaturo-I device
`in urge incontinence shows that five of seven
`patients no longer use pads after a mean
`follow-up of 14.5 months. Confirmation of
`these results in a larger patient group with a
`longer follow-up is awaited.
`
`CONCLUDING REMARKS
`
`Neuromodulation is a valuable treatment
`option for patients with an OAB and
`
`J O U R N A L C O M P I L A T I O N
`
`©
`
`©
`2 0 0 6 T H E A U T H O R
`
` 2 0 0 6 B J U I N T E R N A T I O N A L
`
`Petitioner - Avation Medical, Inc.
`Ex. 1039, p. 46
`
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`E L E C T R I C A L N E U R O M O D U L A T O R Y T H E R A P Y I N F E M A L E V O I D I N G D Y S F U N C T I O N
`
`unobstructive urinary retention. The non-
`surgical techniques can be applied as an
`alternative to standard conservative
`treatment. Neuromodulation should be
`considered before using a more invasive
`operation such as bladder augmentation. It is
`unclear to what extent the various techniques
`are interchangeable.
`
`No variables predictive of success have been
`identified. The determination of reliable
`selection criteria would be a major advance. A
`better understanding of the mechanism of
`action might contribute considerably to this
`goal. Discouraging is the high surgical
`revision rate with the implantable systems;
`this adds to the costs of this type of
`treatment, which are already very high. The
`high costs do not encourage the use of these
`devices at an earlier stage of the disease,
`although this might be preferable to treating
`‘desperate’ cases only. Hopefully, some
`technical advances such as the use of the
`tined lead, the two-stage implant and the
`minimally invasive technique, will decrease
`the need for revision.
`
`CONFLICT OF INTEREST
`
`Ruud Bosch has worked as a study
`investigator for Biocontrol.
`
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`
`©
`2 0 0 6 T H E A U T H O R
`
`J O U R N A L C O M P I L A T I O N
`
`©
`
` 2 0 0 6 B J U I N T E R N A T I O N A L
`
`4 7
`
`Petitioner - Avation Medical, Inc.
`Ex. 1039, p. 47
`
`

`

`B O S C H
`
`for pelvic floor dysfunction. Eur Urol
`2000; 37 (Su