NeuromodulationöSacral, Peripheral and Central: Current Status, Indications, Results and New Developments

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1 EAU Update Series EAU Update Series 2 (2004) NeuromodulationöSacral, Peripheral and Central: Current Status, Indications, Results and New Developments Peter Martin Braun*, Christoph Seif, Christof van der Horst, Klaus-Peter Jünemann Department of Urology, University Hospital Schleswig-Holstein, Campus Kiel, Arnold-Heller-Str. 7, D Kiel, Germany Abstract This article provides basic information on the current status in sacral, peripheral and central neuromodulation techniques. Sacral neuromodulation has been a well-established method for treatment of urinary dysfunction for over 15 years. While it has proved itself to be a long-term successful method of treatment for patients with neurogenic or non-neurogenic overactive bladder (OAB) or chronic retention, many patients are excluded from this beneficial therapy form, as the peripheral nerve evaluation (PNE) test carried out prior to implantation of a permanent neuromodulator still produces non-responder rates of 50% or more. The new two-stage approach developed by Spinelli et al. gives rise to the hope that some problems connected to the PNE test can be overcome through use of the final electrodes during the test. The bion technique, moreover, a brand new technological development for peripheral neuromodulation, may produce new and interesting results in the future. Finally, research is under way for a third neuromodulation approach of direct stimulation in the pontine micturition center, as investigations in Parkinson patients have shown that the incontinence situation can be improved significantly by activation of the deep brain stimulator. # 2004 Elsevier B.V. All rights reserved. Keywords: Neuromodulation; Sacral; Peripheral; Urinary bladder dysfunction 1. Introduction Neuromodulation is a special form of nerve stimulation, used as a therapy option for dysfunctions of the neurological control mechanisms. Sacral or peripheral neuromodulation is an alternative treatment option both for patients with overactive bladder and urinary incontinence that is refractory to conservative anticholinergic drug therapy, and for patients with a hypocontractile detrusor and urinary retention symptoms [1]. The reason why both of these contrary complaints can be treated with the same therapy option lies in the fact that neuromodulation of specific nerve fibres effects continence during the storage phase, while its termination leads to a contraction of the detrusor vesicae. * Corresponding author. Tel: ; Fax: address: pbraun@urology.uni-kiel.de (P.M. Braun). 2. Sacral neuromodulation Initially, an indication for sacral neuromodulation was only proposed in cases of anticholinergic therapyrefractory detrusor instability [2 4]. In the meantime, this strictly limited indication range has been extended to detrusor hypocontractility [5 7] as well as to pain syndromes (such as the pelvic pain syndrome) in the lower urinary tract [8]; the latter indication, however, remains controversial [9,10] since its pathophysiological cause is not fully understood. Moreover, the same technique of electrical stimulation is employed for treatment of anal incontinence, while the mechanism itself probably differs from that which causes the therapeutic effect in dysfunctions of the lower urinary tract [11]. Contraindications for sacral neuromodulation are as follows: anatomical changes of the os sacrum (such as spina bifida) sacral agenesis, trauma residues, stress urinary incontinence, anatomical blad /$ see front matter # 2004 Elsevier B.V. All rights reserved. doi: /j.euus

2 188 P.M. Braun et al. / EAU Update Series 2 (2004) der capacity below 150 ml (measured under anesthesia), pregnancy, incomplete growth period, and finally, a lack of patient compliance. In any case, there should be a peripheral nerve evaluation (PNE) test stimulation prior to implantation of a sacral neuromodulator irrespective of the individual symptom pattern. The respective operating condition of the neuromodulation unit (permanent stimulation/switch-off) affects the bladder activity in different ways: both the storage phase and the voiding phase are supported by the neuromodulator. This phenomenon can be explained by the different stimulating and inhibitory influences on the sympathetic and parasympathetic nerve activities. Afferent muscle spindle fibres of the segments S2 S4 are excited during stimulation. The specific stimulation of a defined group of neurons within the heterogenic axon population of the sacral spinal nerves succeeds through application of low frequency stimulation signals, i.e. too low to reach the threshold potential of other afferent and efferent neurons [12,13]. For simplification of the neuromodulation concept, it is helpful to imagine that a stimulation of these fibres causes the image of a maximally contracted continence unit to be projected to central. In reaction, the sympathetic activity is increased, while the parasympathetic activity of the lower motor neuron of the bladder is decreased. Consequently, activation of the neuromodulation system inhibits the detrusor contractility and can thus be used for therapy of detrusor hyperactivity. Stimulation switch-off, by contrast, triggers the voiding reflex (probably by virtue of a rebound phenomenon), leading to inhibition of the sympathetic activity and simultaneous activation of parasympathetic activity. Uncertainty remains, however, which central area is affected for the detrusor contractions to be inhibited, or for a voiding reflex to be induced. Prior to any implantation of a neuromodulator, the patient should undergo complete urological and neurological diagnosis, including extensive general anamnesis and micturition anamnesis, such as urine tests, physical examination, X-rays of the upper and lower urinary tract and of the os sacrum, urodynamical examinations of bladder function and cystoscopy. These should be performed to rule out other pathologies, to assess the individual condition of the patient, and to quantify the initial dysfunctions as a basis for later comparison with the situation under neuromodulation. The first phase of neuromodulation treatment consists of the percutaneous nerve evaluation test (PNE test) with a stimulation period of 3 to 7 days. Test wire electrodes are placed in the sacral foramen close to the sacral nerve, usually S3 (Fig. 1). The test period serves to establish whether a positive modulation effect can be achieved in the individual patient. If a positive modulation effect meaning subjective and objective improvement of the symptoms by at least 50% is registered, the implantation of a stimulation system Fig. 1. Puncture of the S3 foramen with PNE needle at a 608 angle to the skin to follow the physiological path of the spinal nerve (source: Medtronic Inc.).

3 P.M. Braun et al. / EAU Update Series 2 (2004) Fig. 2. Electrode fixation and final position of the electrodes and the impulse generator. The picture shows the final version with bilateral electrodes. (Source: Medtronic Inc.). ensues: a neuromodulator is placed subcutaneously, gluteal-subcutaneously, or in the hypogastrium and connected to two electrodes stimulating the sacral spinal nerves (Fig. 2). There are some technical variations with respect to the different work groups, which concern the number and the type of the employed electrodes, and more importantly, unilateral vs. bilateral stimulation [14]. In chronic sacral neuromodulation, complication rates of 22% 43% [3,4,15] and reoperation rates of 6% to 50% [4,15,16] are reported. Possible complications in chronic sacral neuromodulation can be divided into operation-related morbidity and hardware problems. The former may involve pain at the implantation site of the electrodes or the impulse generator, electrode migration, wound healing problems and implant infections. Hardware problems occur mainly through electrode fracture, isolation defects and battery exhaustion [4]. In general, the complication rates in acute and subchronic sacral neuromodulation are very low. In some cases the patients sense pain near the site where the wire electrodes have been introduced, or they complain of irritating sensations ( prickle paresthesia ), which is usually only the case if the stimulation currents are maladjusted, i.e. too high. Between June 1997 and June 2002 we performed subchronic neuromodulation tests (PNE tests) in 62 patients (age: 21 to 73, mean age: 53.6; 39 with retention symptoms and 23 with overactive bladder symptoms) over a minimum period of 3 days in order to establish which patients were suitable for chronic neuromodulation. All patients received bilateral PNE test stimulation. In 32 cases out of 62 (51.6%), the PNE test was successful and implantation of a sacral neuromodulator ensued. Their mean age was 52.6 (22 to 68), 20 female and 12 male. The implantation system consisted of Medtronic Synergy Generator 3023 and two quadripolar electrodes for bilateral stimulation. Follow-up took place 3, 6, 9, 12, 18 and 24 months after successful implantation of the neuromodulator. The following aspects were subject to follow-up examination: general physical condition, micturition protocol, sonographic bladder and kidney scans, as well as reassessment of the stimulation parameters. Urodynamical investigations took place after 3, 6, 12 and 24 months. The quality of life was assessed by means of SF-36 Health Survey forms. In both symptom groups (hyperactive bladder and retention) an improvement of the originally reported symptoms was registered both subjectively (patient impression) und objectively (micturition protocol, uro-

4 190 P.M. Braun et al. / EAU Update Series 2 (2004) Fig. 3. Therapeutic results after permanent sacral neuromodulation with bilateral electrode implantation. dynamic results). In the first symptom group (hyperactive bladder), the average number of postoperative incontinence episodes per day decreased by 85%, while the postoperative bladder capacity was increased by 154 ml (49 ml) on average and compliance doubled (Fig. 3) [17]. In the second symptom group (retention) the maximum detrusor pressure increased from 12 cmh 2 O (5 cmh 2 O) to 34 cmh 2 O (14 cmh 2 O), while the amounts of residual urine decreased by 85%. The postoperatively registered amounts of residual urine of 108 ml (33 ml) lead to significantly reduced catheterisation frequencies for the patient (preoperative residual urine: 450 ml 89 ml). Recording of the urodynamic parameters confirmed significant improvement in bladder function (Fig. 3) [17]. In order to make a predictive statement on the therapeutic chances for different patient groups, we classified the 32 PNE-responders, i.e. recipients of permanent neuromodulation units, retrospectively on the basis of their diagnostic characteristics. Out of the 32 PNE-responders, 27 belonged to the group of neurogenic bladder dysfunctions, while the bladder dysfunction was classified as idiopathic in 5 cases. A categorisation on the basis of the parameters retention vs. hyperactive bladder led to a ratio of 20:12. The share of PNE-responders was therefore highest in the diagnostic group neurogenic retention (66.6%), followed closely by the group neurogenic hyperactive bladder (64.3%) [18]. While the overall PNE-success rates could be increased slightly, one in two patients is still classified as a non-responder on the basis of the PNE test. Therefore, our department, as well as a number of other neurourologic centres, are currently testing the new two-stage implantation technique first developed by Spinelli et al. [19,20]: the PNE test is performed with the final stimulation electrodes, which are implanted openly or percutaneously for the test period. These permanent electrodes are connected to an external stimulation device for the test period (Fig. 4). After a successful test phase the electrodes do not have to be not replaced, but can be connected directly to the impulse generator, which is then implanted. This technique allows for the primary electrode to stay exactly in the test position which has proved successful for the patient, thus avoiding the risk of dislocation, inexact repositioning and possibly harmful manipulation in the area of the sacral nerves. The reported success rates are promising and reach up to 90% [19,20]. Moreover, in 8 out of 10 cases Janknegt et al. were able to treat conventional PNE non-responders successfully with the two-stage technique [21]. 3. Peripheral neuromodulation The peripheral approach with an implantable device for pudendal nerve stimulation presents an entirely new neuromodulation method. Currently, the indication is restricted to treatment of overactive bladder dysfunctions. A self-contained, battery-powered mini-neuromodulator with integrated electrode (bion 1, Advanced Bionics Corporation, Valencia, CA, USA; overall electrode size: 26 mm 3 mm) is implanted in the

5 P.M. Braun et al. / EAU Update Series 2 (2004) Fig. 4. Two-stage implantation with permanent leads and external stimulator for extended subchronic testing. (Source: Medtronic Inc.). Alcock s canal close to the pudendal nerve. The potential advantage of this location lies in the fact that the pudendal nerve carries nerve fibers from the sacral segments S2, S3, and S4 therefore urinary bladder dysfunctions might be treated more effectively as more relevant fibres are recruited. The bion 1 can be implanted with a specially developed tool kit over a 3 mm skin incision two fingers medial to the ischial tuberosity. Vaginal or rectal palpation of the ischial spine and X-ray screening helps locate the pudendal nerve, the final stimulation location (Fig. 5). The criteria for a permanent bion 1 implantation are the same as for sacral neuromodulation (50% improvement of symptoms). This is investigated in a percutaneous screening test (PST). In a pilot study, which our department was involved in, 15 PSTs were carried out: 5 female patients showed positive test results with subsequent implantation of a bion 1 for chronic pudendal nerve stimulation. The follow-up visits for the 5 patients were after 180, respectively 90 days. During this period the incontinence episodes decreased from 9.6 to 5.4 per day, resp. 8.2 to 4.3 per day, 4.6 to 1.4 per day, 5.8 to 0.6 per day, and 6.2 to 1.8 per day (average decrease by 61%). The average voiding volume per micturition increased from 103 to 121 ml, resp. 107 to 201, 134 to 135, 188 to 201 and from 164 to 193 ml (average increase by 18%). [22]. 4. Central neuromodulation Neuromodulation has proved a valuable tool in the treatment of anticholinergic therapy refractory urinary bladder dysfunction. Although the exact mechanism of neuromodulation is not fully understood to date, there is experimental evidence of the influence and the role of the pontine micturition centre. The so-called L-region is responsible for urinary storage and the M-region for bladder evacuation. It was possible to prove their connection to the nucleus onuf by means of antegrade cell labelling [23]. In PET studies as well as in recent functional MRI trials, it has been possible to show that a large number of cortical and subcortical centres have a share in the detrusor function and its control mechanisms [24,25]. Moreover, we know that manipulation of the detrusor function through afferent stimulation of the sacral nerves is successful only if the connection to the central micturition centres is fully intact [26]. The efficacy of the treatment of urinary dysfunctions with sacral neuromodulation depends on the residual func-

6 192 P.M. Braun et al. / EAU Update Series 2 (2004) Fig. 5. Method of implantation for a peripheral N. pudendus (bion 1 ) stimulator (Source: Advanced Bionics Corporation). tion of spinal and supraspinal reflex arcs [27]. This theory is supported by the observation that sacral neuromodulation is not or not fully effective in patients with highly incomplete or complete spinal cord lesions [28]. Braun et al. were able to provide experimental evidence that central structures superior to the pons are involved in the filling and voiding function of the bladder, after showing that suprapontine EEG recordings could only be detected in sacral neuromodulation responders [29]. Moreover, Seif et al. confirmed an influence of central thalamic stimulation (subthalamic nucleus stimulation) on the detrusor filling phase in M. Parkinson patients [30]. The study showed that Parkinson patients with activated deep-brain stimulators show a significant increase in bladder capacity and a later occurrence of the first desire to void, while the micturition itself remains unaffected (Fig. 6). It remains unclear, however, in which way the pontine micturition centre is manipulated or controlled by cortical centres at a higher-level, and which role is played by the individual, MRT-detected central areas in urinary storage and voiding. Fig. 6. Comparison of the urodynamic filling and micturition parameters with the STN stimulator switched on and switched off ( * p < 0.005).

7 P.M. Braun et al. / EAU Update Series 2 (2004) Discussion For clinical use sacral neuromodulation has to be considered to be the golden standard which other systems must be compared to. One mayor drawback of the sacral neuromodulation lies in the fact that still a relatively large number of patients, who should profit from this therapy option, are PNE non-responders and are thus excluded from the implantation of a permanent neuromodulation device. A promising development was the study by Kiss et al. who were able to show that the number of non-responders can be reduced to only 10% when permanent stimulation electrodes for the initial test period are used from the start [20]. Since a permanent electrode costs the same amount as 30 PNE test electrodes, we continue to perform a regular PNE test initially. In patients who do not respond to the PNE test but where clinical parameters strongly suggest that the patient would benefit from neuromodulation, we recommend to perform a second test period under employment of a permanent electrode. Peripheral neuromodulation involving the pudendal nerve is known to be effective [31]. The implantable bion 1 system is a new, very similar stimulation electrode device for pudendal nerve neuromodulation. The first results are promising, but long time results must yet prove the efficacy of this system. Treatment with this device should be restricted to neurourology centres despite the fact that the implantation can take place in an out-patient basis and under local anesthesia. The current place of neuromodulation in the therapeutic algorithm must be seen as secondary option after unsuccessful therapy with anticholinergics and more invasive strategies such as urinary diversion. We may safely expect that further basic research and hardware improvements will not only lead to an extension of the indication spectrum, but that neuromodulation will ultimately become the standard therapy option of choice, as unlike the current standard anticholinergic therapy, it has the advantage of few to no side effects for the patient. References [1] Braun PM, Seif C, van der Horst C, Bannowsky A, Bross S, Jünemann KP. Sakrale Neuromodulation: Patientenselektion und Technik. Urologe B 2002;42: [2] Schmidt RA. Applications of neurostimulation in urology. Neurourol Urodyn 1988;7: [3] Shaker H, Hassouna M. Sacral nerve root neuromodulation: an effective treatment for refractory urge incontinence. J Urol 1998;159: [4] Bosch R, Groen J. Sacral (S3) segmental nerve stimulation as a treatment for urge incontinence in patients with detrusor instability: results of chronic electrical stimulation using an implantable neuroprosthesis. J Urol 1995;154: [5] Shaker H, Hassouna M. Sacral root neuromodulation in idiopathic nonob-structive chronic urinary retention. J Urol 1998;159: [6] Jonas U, Grünewald V, Group M-MS. Sacral electrical nerve stimulation for treatment of severe voiding dysfunction. Eur Urol 1999;35:66. [7] Swinn M, Goodwin R, Fowler C. Sacral neuromodulation for young women in urinary retention. Eur Urol 1999;35:17. [8] Schmidt R, Doggweiler R. Neurostimulation and neuromodulation: a guide to selecting the right urological patient. Eur Urol 1998;34(Suppl 1):23 6. [9] Schmidt RA. Urodynamic features of the pelvic pain patient and the impact of neurostimulation on these parameters. World J Urol 2001;19(3): [10] Koldewijn EL, Rosier PF, Meuleman EJ, Koster AM, Debruyne FM, van Kerrebroeck PE. Predictors of success with neuromodulation in lower urinary tract dysfunction: results of trial stimulation in 100 patients. J Urol 1994;152: [11] Matzel KE, Stadelmaier U, Hohenfellner M, Gall FP. Electrical stimulation of the sacral nerves for treatment of incontinence. Lancet 1996;347:63 4. [12] De Groat W, Ryall R. The identification and characteristics of sacral parasympathetic preganglionic neurones. J Physiol Lond 1968;196: [13] Gleason C. Electrophysical fundamentals of neurostimulation. World J Urol 1991;9: [14] Hohenfellner M, Dahms SE, Matzel K, Thüroff JW. Sakrale Neuromodulation der Harnblase. Urologe A 2000;39: [15] Grünewald V, Höfner K, Kuczyk M, Jonas U. Sacral neuromodulation: long-term results of 55 patients with incontinence and voiding dysfunction. Eur Urol 1999;35:16. [16] Koldewijn EL, van Kerrebroeck PE, Meuleman EJ, Bemelmans B, Debruyne FM. Neuromodulation effective in voiding dysfunction despite high percentage of reoperations. Eur Urol 1999;35:15. [17] Braun PM, Seif C, Scheepe JR, Martinez Portillo FJ, Bross S, Alken P, et al. Chronic sacral bilateral neuromodulation. Using a minimal invasive implantation technique in patients with disorders of bladder function. Urologe A 2002;41:44 7 (in German). [18] Seif C, Eckermann J, Bross S, Martinez FJ, Jünemann KP, Braun PM. Findings with bilateral sacral neurostimulation: Sixty-two PNE-tests in patients with neurogenic and idiopathic bladder dysfunctions. Neuromodulation 2004;7: [19] Spinelli M, Giardiello G, Arduini A, van den Hombergh U. New percutaneous technique of sacral nerve stimulation has high initial success rate: preliminary results. Eur Urol 2003;43:70 4. [20] Kiss G, Rehder P, Madersbacher H. Modified PNE testing with permanent electrodes gives better results. Eur Urol Suppl 2002;1(1):143 [Abstract 562]. [21] Janknegt RA, Weil EH, Eerdmans PH. Improving neuromodulation technique for refractory voiding dysfunctions: two-stage implant. Urology 1997;49: [22] Bosch R, Buller J, Groen J. Treatment of refractory urge urinary incontinence by a novel minimally invasive implantable pudendal nerve mini-stimulator. Eur Urol Suppl 2004;3(2):49 [Abstract 186]. [23] Blok BF, Holstege G. Two pontine micturition centers in the cat are not interconnected directly: implications for the central organization of micturition. J Comp Neurol 1999;403(2):

8 194 P.M. Braun et al. / EAU Update Series 2 (2004) [24] Blok BF. Brain control of the lower urinary tract. Scand J Urol Nephrol Suppl 2002;210:11 5. [25] van der Horst C, Kuhtz-Buschbeck JP, Pott C, Wolff F, Nabavi A, Jansen O, Jünemann KP, Braun PM. Cortical control over perception of urinary urge. Urologe A 2004;(Suppl 1): P5.13. [26] Malaguti S, Spinelli M, Giardiello G, Lazzeri M, Van Den Hombergh U. Neurophysiological evidence may predict the outcome of sacral neuromodulation. J Urol 2003;170(6 Pt 1): [27] Schurch B, Reilly I, Reitz A, Curt A. Electrophysiological recordings during the peripheral nerve evaluation (PNE) test in complete spinal cord injury patients. World J Urol 2003;20(6): [28] Schmidt R, Doggweiler R. Neurostimulation and Neuromodulation: a guide to selecting the right urological patient. Eur Urol 1998; 34(Suppl 1):23 6. [29] Braun PM, Baezner H, Seif C, Boehler G, Bross S, Eschenfelder CC, et al. Alterations of cortical electrical activity in patients with sacral neuromodulator. Eur Urol 2002;41(5): [30] Seif C, Herzog J, van der Horst C, Schrader B, Volkmann J, Deuschl G, et al. Effect of subthalamic deep brain stimulation on the function of the urinary bladder. Ann Neurol 2004;55(1): [31] Knoll M, Madersbacher H, Ebner A. Therapie der Detrusorhyperaktivität durch perkutane Elektrostimulation des Nervus pudendus. Aktuel Urol 1992;23: CME questions Please visit to answer these CME questions on-line. The CME credits will then be attributed automatically. 1. The following diseases present no indication for sacral neuromodulation treatment: A. interstitial cystitis, B. idiopathic detrusor hyperactivity, C. stress urinary incontinence, D. neurogenic detrusor hypoactivity. 2. For a positive PNE test result, the subjective and objective improvement of urinary symptoms should be at least: A. 33%, B. 50%, C. 75%, D. 100%. 3. Which location is not suitable for peripheral neuromodulation: A. Nucl. subthalamicus, B. N. dorsalis penis, C. N. pudendus, D. N. tibialis anterior. 4. In the two-stage approach of sacral neuromodulation A. the test phase is always performed unilaterally, B. the permanent stimulation electrodes are used for the testing period, C. the permantent electrodes cannot be removed after a negative testing period, D. the testing phase is limited to three days.