Acute Urodynamic Effects of Posterior Tibial Nerve Stimulation on Neurogenic Detrusor Overactivity in Patients with MS

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1 european urology 51 (2007) available at journal homepage: Neuro-urology Acute Urodynamic Effects of Posterior Tibial Nerve Stimulation on Neurogenic Detrusor Overactivity in Patients with MS Morten V. Fjorback a, *, Farida S. van Rey b, Floor van der Pal b, Nico J.M. Rijkhoff a, Thor Petersen c, John P. Heesakkers b a Center for Sensory Motor Interaction (SMI), Aalborg University, Aalorg, Denmark b Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands c The Centre for Multiple Sclerosis in Ry, Ry, Denmark Article info Article history: Accepted July 20, 2006 Published online ahead of print on August 7, 2006 Keywords: PTNS Electrical stimulation Neuromodulation Multiple sclerosis Incontinence Abstract Objectives: The aim of this study was to investigate whether acute electrical stimulation of the posterior tibial nerve could suppress detrusor contractions in multiple sclerosis (MS) patients with neurogenic detrusor overactivity. Methods: Two successive slow-fill cystometries (16 ml/min) were carried out in eight MS patients with neurogenic detrusor overactivity. The first filling served as control without stimulation. In the second filling, electrical stimulation using needle electrodes was applied automatically to the posterior tibial nerve when the detrusor pressure exceeded 10 cm H 2 O. An additional filling in which the needle electrodes were replaced by surface electrodes was carried out in three patients. Results: The control filling showed detrusor overactivity in eight patients, but electrical stimulation of the posterior tibial nerve failed to suppress detrusor contractions in all tested patients. Conclusions: Although neuromodulative effects may be obtained with therapeutic electrical stimulation of the posterior tibial nerve, no acute effects were demonstrated. For this reason, electrical stimulation of pudendal afferents remains the only option if acute suppression of a detrusor contraction is required. # 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. Center for Sensory Motor Interaction (SMI), Department of Health Science and Technology, Aalborg Universitet, Frederik Bajersvej 7, D2, 9220 Aalborg Oest, Denmark. Tel address: mvf@smi.auc.dk (M.V. Fjorback) /$ see back matter # 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi: /j.eururo

2 european urology 51 (2007) Introduction The most common urologic disorder in multiple sclerosis (MS) is neurogenic detrusor overactivity (NDO), which develops in 62% of all MS patients [1]. The main symptoms of NDO include urgency, increased daytime frequency, nocturia, and urge urinary incontinence. These symptoms influence the patient s quality of life because of social and hygienic difficulties. If patients are refractory to pharmacologic treatment of NDO or cannot tolerate the side effects, repeated intramuscular injections of botulinum toxin into the detrusor, sacral neuromodulation, or intravesical instillation with vanilloids could be considered [2,3]. If satisfactory results cannot be obtained otherwise, surgical intervention such as augmentation cystoplasty, incontinent vesicostomy, or urinary diversion may be applied. Since the neurologic symptoms of MS change over time together with the urologic disorders, a nondestructive treatment option would be preferred to avoid or postpone destructive surgery. Electrical stimulation of the dorsal penile nerve (DPN) has been used to suppress detrusor contractions and increase bladder capacity in spinal cord injured patients [4 6] and in patients with MS [7]. However, long-term use of surface electrodes in the genital region may not be well tolerated and may introduce hygienic challenges. For this reason, electrical stimulation of the posterior tibial nerve may be an alternative [8 13]. In principle, inhibition of a detrusor contraction is needed only in case of an involuntary detrusor contraction, and electrical stimulation can thus be initiated when intravesical pressure starts to rise and can be stopped when the pressure has returned to baseline. This technique is called conditional or event-triggered stimulation. Conditional stimulation of the dorsal penile/clitoral nerve has been shown to be as least as effective as continuous Fig. 1 Method of connecting portable device, stimulator, transducers, and catheters to a male subject. Electrodes were placed in a similar fashion on the contralateral leg.

3 466 european urology 51 (2007) stimulation and may reduce habituation of the involved reflex arches while extending the battery life of the stimulator [4]. Previous studies using stimulation of the posterior tibial nerve have focused on the effect of weekly therapeutic stimulation [10 13] or continuous stimulation during urodynamics [11]. The aim of this study was to investigate the acute effects of posterior tibial nerve stimulation during urodynamics. 2. Materials and methods The study was approved by the local ethics committee in Denmark and in Nijmegen, The Netherlands, and informed consent was obtained from the 12 patients (7 men, 5 women) with an average age of 46 yr (range: 32 63) who participated in this study. The inclusion criterion was MS patients with a previous (within a year) urodynamic study showing detrusor overactivity and a maximum cystometric capacity <300 ml. Exclusion criteria were sacral peripheral nerve lesions, urinary tract infection, serious secondary disease, and an expanded disability status scale score of >7. The majority of patients were refractory to pharmacologic treatment of NDO, but three patients who were using anticholinergics (Tolterodine) were asked to stop the treatment a week prior to the experiments. All experiments were done with the patient in the supine position. Intravesical and abdominal pressures were measured with a fluid-filled, CH 8, double lumen catheter and a rectal balloon catheter together with TruWave transducers (Edwards Lifesciences, Irvine, CA, USA), as shown in Fig. 1. All pressure data, sampled at 20 Hz, were collected with a custommade portable device for ambulatory urodynamic monitoring [6]. The detrusor pressure was calculated as the difference between the intravesical and abdominal pressure (P ves P abd ). Two successive slow-fill cystometries (16 ml/min) were carried out in each patient with saline at room temperature if detrusor overactivity was observed in the first filling (control filling). The filling order was not randomized to prevent carryover effects from fillings in which stimulation was applied to affect the control filling. In the second filling, conditional electrical stimulation of the posterior tibial nerve was applied bilaterally with 34-gauge stainless steel needles (cathodes) inserted 5 cm cephalad from the medial malleolus and posterior to the edge of the tibia, as shown in Fig. 1. Round, 32-mm surface electrodes (Axelgaard Manufacturing Co, Fallbrook, CA, USA) were placed bilaterally over the medial aspect of the calcaneus (anodes). Electrical stimulation was applied bilaterally by using charge-compensated 200-ms pulses with a pulse rate of 20 Hz, as used in previous studies [12,13]. Prior to the start of recording, electrical stimulation was triggered with a push button to determine the appropriate stimulation amplitude and to confirm correct needle placement. The stimulation amplitude was set at the maximum tolerable level according to the subject under investigation, which was usually 1.5 times the threshold for evoking plantar flexion of the toes and/or toe fanning (range: 1 5 ma). An additional filling in which the needle electrodes were replaced by surface electrodes was carried out in three patients at the maximum tolerable level (range: ma). Electrical Fig. 2 Detrusor pressure and estimated bladder volume in patient 1. The detrusor pressure and estimated bladder volume are shown at each point in time. During the control session (without stimulation), a detrusor contraction occurred that resulted in leakage (A). Bilateral stimulation of the posterior tibial nerve with either needle (B) or surface (C) electrodes was unable to suppress a detrusor contraction, and leakage occurred during contraction. The amplitude and shape of the time/ pressure curve were similar in all three fillings, but each successive filling resulted in increased volume at first contraction.

4 european urology 51 (2007) Fig. 3 Detrusor pressure as a function of time from the second filling in which stimulation was applied with needle electrodes in eight patients. The arrows indicate the onset of leakage, and the bars beneath each tracing indicate that stimulation was applied. stimulation was applied automatically in both the second and third fillings whenever the detrusor pressure exceeded 10 cm H 2 O and was stopped automatically if the pressure remained <10 cm H 2 O for more than 10 s [7]. The urodynamic output measures were the volume at first involuntary detrusor contraction, the maximum detrusor pressure, and the volume at which leakage occurred. Patients reported the perception of the stimulation during recording together with the sensation of urgency. Bladder filling was stopped and the bladder emptied if leakage occurred during stimulation or the patient was uncomfortable. Leaked fluid was collected in a diaper, and the volume was measured by weighing the diaper. The bladder was emptied through the catheter after each filling to determine the residual volume. 3. Results The control filling showed detrusor overactivity in 8 of the 12 patients. Stimulation was not applied in the four patients who did not present with NDO. Fig. 2 shows an example of the data recorded in a single patient. Conditional electrical stimulation of the posterior tibial nerve with either needle or surface electrodes was unable to suppress a detrusor contraction in any patient, and no reduction of urgency was reported during stimulation. Fig. 3 shows the data from the eight patients in whom the posterior tibial nerve was stimulated. Phasic detrusor overactivity was observed in patients 3, 4, 5, 7, and 8, whereas the remaining patients showed terminal detrusor overactivity. Although stimulation was applied, the first detrusor contraction resulted in leakage in patients 1, 6, and 8. No leakage occurred in patients 2 and 4, but stimulation was unable to suppress the contractions. In patients 3, 5, and 7, the detrusor pressure decreased during stimulation. A decrease in pressure could imply an inhibitory effect caused by stimulation. However, this observation may not be the case, since the control filling in each of these patients showed a similar pressure pattern (Fig. 4). In all patients, the peak pressure during stimulation of the posterior tibial nerve was similar to the peak pressure during contraction in the control fillings (Table 1). No significant difference was found with the Wilcoxon signed rank test ( p = 0.48). The repeated fillings in each patient were associated with increased volume at the first undesired detrusor contraction, as shown in Table 1. The median volume at first contraction in the second filling was 36% higher than in the control filling, and a Wilcoxon signed rank test showed that the increase was statistically significant ( p = ). 4. Discussion Electrical stimulation of the posterior tibial nerve with needle electrodes was unable to suppress a detrusor contraction in any of the eight stimulated

5 468 european urology 51 (2007) Fig. 4 Data from the first and second filling in patients 3, 5, and 7. The arrows indicate the onset of leakage, and the bars beneath each tracing indicate that stimulation was applied. patients, and no reduction of urgency was reported during stimulation. Detrusor contractions could not be suppressed with surface electrode stimulation in the three patients in whom this was tested. Previous studies have reported an increase in volume at first contraction together with an increase in cystometric bladder capacity when stimulation was applied during cystometry [9,11,14]. In a group of 22 patients with either NDO or idiopathic detrusor overactivity, treatment with posterior tibial nerve stimulation was considered successful in the majority of patients and was found to abolish urgency [9]. In a single case study, an increase in cystometric capacity was reported in a spinal cord-injured subject, but detrusor contractions were not found to recur immediately after stimulation was stopped [14]. In another study of 37 patients with NDO, it was concluded that stimulation was associated with a significant increase in volume at the first involuntary detrusor contraction of 50% together with an increase in maximum cystometric capacity [11]. However, it is not clear whether these results are caused by stimulation or by the repeated bladder fillings at nonphysiologic rates. A 36% increase in volume at the first contraction was found in our study on eight patients, although no stimulation was applied until the contraction had already started. This finding suggests that the increase in volume at first contraction at least is not due only to stimulation. Detrusor inhibition was not obtained in our study with the use of a 20-Hz pulse rate, but stimulation with a lower pulse rate may provide stronger detrusor inhibition. For this reason we tested a pulse rate of 10 Hz in an additional MS patient who was not included in the current study. Stimulation at 10 Hz also failed to suppress any involuntary bladder contractions. Our findings are supported by a study in which conditional stimulation of the anal sphincter suppressed detrusor contractions in 11 of 15 spinal cord-injured subjects, but use of peroneal or tibial nerve stimulation failed to suppress any contractions [15]. A study using a spinal animal model concluded that stimulation amplitude had to be above the threshold for a motor response to obtain acute suppression [16]. However, another animal study reported that acute tibial nerve stimulation was ineffective in five unanaesthetized and spinalized cats, and increased bladder activity because of leg spasms [17]. Our study showed that bilateral posterior tibial nerve stimulation using an amplitude of 1.5 times the motor threshold does not cause acute detrusor inhibition in MS patients with NDO. In addition, no reduction in urgency was reported by any patient. We decided to use bilateral stimulation to maximize the number of depolarized tibial nerve afferents and, at the same time, to make sure that the lack of inhibition was not caused by asymmetric

6 european urology 51 (2007) Table 1 Bladder volume at first contraction and maximum detrusor pressure during stimulation (if applied) in the three fillings performed in each patient Patient no. Volume at first contraction (ml) Maximum detrusor pressure (cm H 2 O) 1st filling 2nd filling 3rd filling 1st filling 2nd filling 3rd filling Median innervation. Since stimulation was applied at the maximum tolerable level according to each patient, it was not possible to depolarize a higher number of tibial nerve afferents, which may increase the inhibitory effect of stimulation. Although inhibition through a direct route in the sacral cord may not be present, it does not rule out the possibility of a neuromodulatory effect that may provide symptomatic relief in patients with NDO when stimulation is applied therapeutically. Several studies have investigated the effect of weekly half-hour stimulation sessions of the posterior tibial nerve in patients with detrusor overactivity [10,12,13,18,19]. Inthreestudies,subjective success rates of 56%, 60%, and 64% were reported on the basis of the patients desire to continue treatment [10,13,19]. Objective success rates of 32.6%, 56%, and 71% on the basis of a 50% reduction in the number of daily leakage episodes or a 25% reduction in daytime and/or nighttime frequency were also reported [10,12,19]. Although these results are promising, placebo-controlled studies are needed to confirm that these results are caused by stimulation only. The fact that bad mental health can be used as a negative prognostic factor for the success of tibial nerve stimulation also indicates that involvement of suprasacral structures may explain the failure of inhibition in patients with NDO [19]. The primary weakness of this study is the low number of tested patients. Only 8 of 12 patients were tested with tibial nerve stimulation. The other four patients did not show NDO during the fist filling. A previous urodynamic study (less than a year prior to the study) had shown NDO in these patients, which stresses the fact that destructive treatment options should be avoided in MS patients, since the urologic symptoms change over time [20]. Neurophysiologic assessment was not performed in the patients, and unknown peripheral nerve lesions cannot be excluded as an explanation for the lack of inhibition. Because of time constraints, a third filling was performed in only three patients, which makes these data inconclusive. Since conditional stimulation of the posterior tibial nerve was unable to cause acute suppression of a detrusor contraction, it leaves DPN stimulation as the best option for a surface electrode-based conditional system. More invasive methods may be required to achieve user acceptance. One option could be to stimulate the pudendal nerve using implantable electrodes. To date it has been difficult to place and maintain an electrode in close proximity to the pudendal nerve in man. Recent advances in technology may solve such problems [21,22]. Pudendal nerve stimulation allows activation of pudendal afferents from all three sacral segments together with activation of efferents innervating the external urethral sphincter and pelvic floor muscles. The ultimate goal of our work is to develop an implantable neuroprosthetic device for rehabilitation of detrusor overactivity. A major challenge with respect to the conditional stimulation still remains, since the sensing of pressure using a urethral catheter cannot be used as a long-term solution. This problem is far from trivial, and more research is needed in the field of natural [23] or artificial sensors to overcome this challenge. When this problem is solved, an automatic closed-loop electrical stimulation system may lead to increased performance over open-loop systems. Alternatively, it may be possible for MS patients to activate stimulation themselves, thus eliminating the need for automatic stimulation [7,24]. Besides MS patients, other patients with neurogenic bladder dysfunction may respond appropriately to such a treatment if their sacral reflexes are intact.

7 470 european urology 51 (2007) Conclusions Although therapeutic effects from stimulating the posterior tibial nerve may be present, we were unable to demonstrate any acute effects during urodynamics in patients with MS. For this reason, stimulation of the posterior tibial nerve is not an alternative to DPN stimulation in a system that relies on the acute inhibition of a detrusor contraction. One could consider electrical stimulation with implanted electrodes to avoid the disadvantages of using surface electrodes in the genital region. Acknowledgements This study was funded by the Danish Research Foundation and the Danish Multiple Sclerosis Society. References [1] Litwiller SE, Frohman EM, Zimmern E. Multiple sclerosis and the urologist. J Urol 1999;161: [2] Schurch B, de Seze M, Denys P, et al. Botulinum toxin type a is a safe and effective treatment for neurogenic urinary incontinence: results of a single treatment, randomized, placebo controlled 6-month study. J Urol 2005;174: [3] Hohenfellner M, Humke J, Hampel C, et al. Chronic sacral neuromodulation for treatment of neurogenic bladder dysfunction: long-term results with unilateral implants. Urology 2001;58: [4] Kirkham APS, Shah NC, Knight SL, Shah PJ, Craggs MD. The acute effects of continuous and conditional neuromodulation on the bladder in spinal cord injury. Spinal Cord 2001;39: [5] Hansen J, Media S, Nohr M, Biering-Sørensen F, Sinkjær T, Rijkhoff NJ. Treatment of neurogenic detrusor overactivity in spinal cord injured patients by conditional electrical stimulation. J Urol 2005;173: [6] Fjorback MV, Hansen J, Dalmose AL, Rijkhoff NJM, Sinkjaer T. A portable device for experimental treatment of neurogenic detrusor overactivity. Neuromodulation 2003; 6: [7] Fjorback MV, Rijkhoff NJM, Petersen T, et al. Event driven electrical stimulation of the dorsal penile/clitoral nerve for management of neurogenic detrusor overactivity in multiple sclerosis. Neurourol Urodyn 2006;25: [8] Cooperberg MR, Stoller ML. Percutaneous neuromodulation. Urol Clin North Am 2005;32:71 8. [9] Mcguire EJ, Shi-chun Z, Horwinski ER, Lytton B. Treatment of motor and sensory detrusor instability by electrical stimulation. J Urol 1983;129:78 9. [10] Vandoninck V, Van Balken MR, Finazzi AE, et al. Posterior tibial nerve stimulation in the treatment of urge incontinence. J Urol 2003;169: [11] Amarenco G, Ismael SS, Even-Schneider A, et al. Urodynamic effect of acute transcutaneous posterior tibial nerve stimulation in overactive bladder. J Urol 2003;169: [12] Govier FE, Litwiller S, Nitti V, Kreder KJ, Rosenblatt P. Percutaneous afferent neuromodulation for the refractory overactive bladder: results of a multicenter study. J Urol 2001;165: [13] Van Balken MR, Vandoninck V, Gisolf KWH, et al. Posterior tibial nerve stimulation as neuromodulative treatment of lower urinary tract dysfunction. J Urol 2001;166: [14] Andrews BJ, Reynard JM. Transcutaneous posterior tibial nerve stimulation for treatment of detrusor hyperreflexia in spinal cord injury. J Urol 2003;170:926. [15] Vereecken RL, Das J, Grisar P. Electrical sphincter stimulation in the treatment of detrusor hyperreflexia of paraplegics. Neurouol Urodyn 1984;3: [16] van der Pal F, Grill W, Gustafson K, Heesakkers J, Debruyne F, Bernelmans B. Acute tibial nerve stimulation to suppress bladder contractions in the cat. Presented at the International Continence Society 34th annual meeting, Paris, France, 2004 Aug (abstract no. 500). [17] Walter JS, Wheeler JS, Robinson CJ, Wurster RD. Inhibiting the hyperreflexic bladder with electrical stimulation in a spinal animal model. Neurourol Urodyn 1993;12: [18] Congregado Ruiz B, Pena Outeiriño XM, Campoy Martínez P, León Dueñas E, Leal López A. Peripheral afferent nerve stimulation for treatment of lower urinary tract irritative symptoms. Eur Urol 2004;45:65 9. [19] van Balken MR, Vergunst H, Bemelmans BLH. Prognostic factors for successful percutaneous tibial nerve stimulation. Eur Urol 2006;49: [20] Ciancio SJ, Mutchnik SE, Rivera VM, et al. Urodynamic pattern changes in multiple sclerosis. Urology 2001;57: [21] Spinelli M, Malaguti S, Giardiello G, Lazzeri M, Tarantola J, Van Den Hombergh U. A new minimally invasive procedure for pudendal nerve stimulation to treat neurogenic bladder: description of the method and preliminary data. Neurourol Urodyn 2005;24: [22] Groen J, Amiel C, Bosch JL. Chronic pudendal nerve neuromodulation in women with idiopathic refractory detrusor overactivity incontinence: results of a pilot study with a novel minimally invasive implantable mini-stimulator. Neurourol Urodyn 2005;24: [23] Kurstjens M, Rijkhoff NJM, Borau A, Rodriguez A, Vidal J, Sinkjaer T. Intraoperative recording of sacral root nerve signals in humans. Artif Organs 2005;29: [24] Lee YH, Creasey GH. Self-controlled dorsal penile nerve stimulation to inhibit bladder hyperreflexia in incomplete spinal cord injury: a case report. Arch Phys Med Rehab 2002;83:273 7.

8 european urology 51 (2007) Editorial Comment Massimo Lazzeri, Department of Urology, Casa di Cura Santa Chiara Firenze, Italy Fjorback and colleagues reported the acute urodynamic effects of electrical stimulation of the posterior tibial nerve in a selected group of multiple sclerosis (MS) patients suffering from neurogenic detrusor overactivity. A small, but adequately homogeneous group of 12 patients with detrusor overactivity, received three successive filling cystometries: the control cystometry (no stimulation) and afterwards the second and third cystometry under electrical stimulation using needle and surface electrodes respectively. The electrical stimulation was conditionally applied to the posterior tibial nerve when the detrusor pressure exceeded 10 cmh2o. Unfortunately they found that electrical stimulation of the posterior tibial nerve failed to suppress detrusor contractions in all patients. In the last two decades, many of urologists involved in the treatment of functional disorders of the lower urinary tract have investigated different methods to stimulate a safe and easy method in the peripheral nervous system and encouraging results were reported for different techniques, different devices and different nerves stimulated [1]. In the field of electrical modulation, only few manuscripts deal with negative results, while many papers contain useful guidelines and recommendations about the positive effect of these techniques for different disorders spanning from idiopathic urinary retention, overactive bladder syndrome and painful bladder syndrome. Generally many of the positive effects seem sensible, worthy, and helpful for daily clinical practice and such scientific encouragement alone can substantially improve the interest and the application of electrical device by health-care professionals. Little work has been published showing evidence of bad results because it is thought to increase frustration and dissatisfaction among doctors and patients. We have to congratulate the authors for reporting negative results. Generally new therapies are supposed to be better than the treatment they replace and not to induce any side effects. In the era of high tech medicine there are several occasions, in which reporting good results is a sure path to publication and citation success in certain circles. Here authors stated negative results, which could have important consequences in the field of electrical modulation research for detrusor overactivity treatment. Reference [1] van Balken MR, Vergunst H, Bemelmans BL. The use of electrical devices for the treatment of bladder dysfunction: a review of methods. J Urol 2004;172: Editorial Comment Axel Haferkamp, André Reitz, Department of Urology, University of Heidelberg, INF 110, Heidelberg, Germany With interest we have read the study by Fjorback et al. on the acute urodynamic effects of posterior tibial nerve stimulation on neurogenic detrusor overactivity in patients with multiple sclerosis. The authors report on a small group of patients with neurogenic detrusor overactivity presenting with urgency, increased daytime frequency, nocturia, and urge urinary incontinence. As stated in the article, acute urodynamic electrical stimulation of the posterior tibial nerve did not suppress detrusor contractions in patients with multiple sclerosis. However, several studies on tibial nerve stimulation reported subjective improvement and reduction of incontinence episodes and daytime and nighttime frequency in both neurogenic and nonneurogenic patients. This implies that there might be an inhibitory effect on detrusor overactivity, but this effect may not necessarily be seen during urodynamic studies. This study has major drawbacks. The authors did not present any clinical or neurophysiologic data on their patients. Simple clinical sacral or tibial reflex provocations, sensory testings of the lumbar and sacral dermatomes, neurophysiologic recordings of the pudendal and tibial reflexes, or nerve conduction velocities are missing; thus, the reader is not able to appraise the current neurologic status of the studied patients. Because multiple sclerosis potentially affects all parts of the nervous system (somatic and autonomic pathways on the peripheral, spinal, and supraspinal levels), a peripheral nerve lesion or a sacral spinal

9 472 european urology 51 (2007) lesion would prevent any improvement in these patients. Furthermore, no data are given about the history of the disease in the studied population. From the range of age (32 63 yr), one would expect a heterogeneous population with both mild and advanced disease. Thus, the responses to the stimulation are difficult to compare because young patients with only mild symptoms may respond better to the stimulation than patients with advanced disease and long-term severe urinary symptoms. In the light of these two points and the limited number of patients evaluated, the claim of the authors that electrical stimulation of the posterior tibial nerve does not suppress detrusor contractions in patients with multiple sclerosis seems excessive. Further research on the neurophysiologic effects of tibial nerve stimulations is necessary and welcomed.