Editorial Manager(tm) for The Journal of Urology Manuscript Draft Manuscript Number: JU-09-2011 Title: Transcutaneous Electrical Nerve

Stimulation in Children with Overactive Bladders: A Randomized Clinical Trial Article Type: Pediatric Article Keywords: Transcutaneous eletric nerve stimulation, overactive bladder, children, nocturnal enuresis, urinary tract infection Corresponding Author: Dr. Ubirajara Barroso Jr., MD Corresponding Author's Institution: Federal University of Bahia and Baiana School of Medicine and Public Health First Author: Patrcia Lordlo, Professor of Physiothrerapy Order of Authors: Patrcia Lordlo, Professor of Physiothrerapy; Alcina Teles, Professor; Maria Luiza Veiga, Professor; Luis Claudio Correia, Professor; Ubirajara Barroso Jr., MD Manuscript Region of Origin: BRAZIL Abstract: Objective: To evaluate the effectiveness of parasacral transcutaneous electrical nerve stimulation (PSTENS) in the treatment of bladder overactivity in children. This evaluation was realized though a randomized clinical trial. Material and Methods: In a prospective, randomized clinical trial and blind study, 37 children - 25 girls and 12 boys - with an average age of 7. 6 years (4 - 12) - were separated in two groups - the test group (PSTENS) and the sham group (superficial scapular electrical stimulation). A total of twenty, 20 minute sessions (10 Hz) were performed 3 times a week. The following criteria was used to evaluate the rate of success: 1) self reported cure, significant, mild or no improvement; 2) analogical visual scale (AVS - level of success measured on a scale from 0 to 10); 3) % of improvement; 4)a modified score of Toronto; 5) the values for maximum voiding volume (MVV), average voiding volume (AVV) and average urinary frequency encountered in the bladder diary. After the completion of the twenty sessions, the patients of the SG who were not cured underwent PSTENS treatment. Results: 21 in the test group and 16 in the sham group underwent treatment. In the TG, 61.9% of the parents reported cure. In the sham group, no parents reported cure (p<0,001). In the evaluation of the AVS values recorded in the test group, 13 parents indicated a 10 and in the sham group, one indicated a 9. Considering the percentage of improvement, 12 parents in the test group had 100% while no one in the sham group had 100%. The score of Toronto improved significantly in the test group and in the sham group (p<0.001 and p=o.008, respectively). However the score was reduced more significantly in the test group in comparison with the sham group, p = 0,011. In the test group, the values of AVV and MVV presented a statistically significant increase and the values for average urinary frequence decreased. After superficial scapular electrical stimulation, 13 of the 16 patients who underwent PSTENS were cured. Conclusions: This is the first randomized clinical trial to prove that PSTENS is effective in the treatment of children with overactive bladders.

Suggested Reviewers: Piet Hoebeke MD Professor, Pediatric Urology, Ghent University Piet.Hoebeke@uzgent.be He was the first to publish on parasacral TENS and he has other papers on tibial posterior stimulation and overactive bladder in children Opposed Reviewers:

Cover Letter

Dear Mr. Editor,

We are submitting the paper entitled Transcutaneous Electrical Nerve Stimulation in Children with Overactive Bladders: A Randomized Clinical Trial for the evaluation and possibly be published in the Journal of Urology

Yours Sincerely,

Ubirajara Barroso Jr.

*Manuscript (Submit in MS Word; Tables and Figures should NOT be included but attached separately)

Transcutaneous Electrical Nerve Stimulation in Children with Overactive Bladders: A Randomized Clinical Trial

Patrcia Lordlo, Alcina Teles, Maria Luiza Veiga, Luis Cludio Correia, Ubirajara Barroso Jr.*

Department of Urology and Physical Therapy, Section of Pediatric Urology, Bahiana School of Medicine

Correspondence Ubirajara Barroso Jr. Av. Juracy Magalhes Jr.,2096 Rio Vermelho 41940060 Salvador Bahia Brazil

ABSTRACT Objective: To evaluate the effectiveness of parasacral transcutaneous electrical nerve stimulation (PSTENS) in the treatment of bladder overactivity in children. evaluation was realized though a randomized clinical trial. Material and Methods: In a prospective, randomized clinical trial and blind study, 37 children 25 girls and 12 boys with an average age of 7. 6 years (4 - 12) - were separated in two groups the test group (PSTENS) and the sham group (superficial scapular electrical stimulation). A total of twenty, 20 minute sessions (10 Hz) were performed 3 times a week. The following criteria was used to evaluate the rate of success: 1) self reported cure, significant, mild or no improvement; 2) analogical visual scale (AVS level of success measured on a scale from 0 to 10); 3) % of improvement; 4)a modified score of Toronto; 5) the values for maximum voiding volume (MVV), average voiding volume (AVV) and average urinary frequency encountered in the bladder diary. After the completion of the twenty sessions, the patients of the SG who were not cured underwent PSTENS treatment. Results: 21 in the test group and 16 in the sham group underwent treatment. In the TG, 61.9% of the parents reported cure. In the sham group, no parents reported cure (p<0,001). In the evaluation of the AVS values recorded in the test group, 13 parents indicated a 10 and in the sham group, one indicated a 9. Considering the percentage of improvement, 12 parents in the test group had 100% while no one in the sham group had 100%. The score of Toronto improved significantly in the test group and in the sham group (p<0.001 and p=o.008, respectively). However the score was reduced more significantly in the test group in comparison with the sham group, p = 0,011. In the test group, the values of AVV and MVV presented a statistically significant increase and the values for average urinary frequence decreased. After superficial scapular electrical stimulation, 13 of the 16 patients who underwent PSTENS were cured. Conclusions: This is the first randomized clinical trial to prove that PSTENS is effective in the treatment of children with overactive bladders. This

Key words: transcutaneous electrical stimulation, urinary incontinence, bladder, child

This work received grants from Fundao de Amparo a Pesquisa do Estado da Bahia (from the government of Bahia State Brazil).

Introduction

Lower urinary tract dysfunction (LUTD) is a disturbance found in neurologically normal children and can occur in both the filling and in the emptying phases of the lower urinary tract.1 Overactive bladder (OAB) is clinically characterized by urgency, daytime urinary incontinence and it is often associated with frequency.1 Daytime

urinary incontinence in 7 year old children was found to be 3.5% in boys and 6% in girls. 2 Urgency was detected in 20% of these children. Daytime incontinence is a source of psychological stress and social discomfort which in turn, lowers a childs self esteem.3;4 Moreover, LUTD is associated to urinary tract infection (UTI), vesicoureteral reflux,5;6 and presents a risk of renal scarring in children7;8. Antimuscarinics are frequently used to treat OAB in children. However, for oxibutinyn, (the most commonly used medication from this group), there is no randomized clinical trial.9 One randomized clinical trial evaluated the role of tolterodine in children with OAB and found no difference in the outcome between the test group and the placebo10. Electrical stimulation was introduced as an alternative to treat OAB in children. Hoebeke et al. and Bower et al. first described the use of para sacral transcutaneous electrical neural stimulation (PSTENS) in children with refractory OAB and found good results with daily sessions during a period of 5 to 6 months.
11,12

We were the first to

report a short course PSTENS in children. Treatments were scheduled 3 times a week for a maximum of 20 sessions. The short term results indicated a complete response for 63% of the cases and significant improvement of symptoms for 32 % of the cases. 13 We

evaluated our long term results with this procedure. With a mean follow up of 35.3 monts (range 6 to 80), continued success was seen in 78% of the children.14 Both studies were performed without a control group. The aim of the current study is to evaluate the efficacy of the PSTENS in the OAB in children in a randomized clinical trial.

Material and Methods

This is a prospective controlled randomized clinical trial in which the participants were children with OAB that were more than 4 years old. OAB was defined as the presence of characteristic symptoms such as urgency, with or without daytime incontinence, accompanied by holding maneuvers to avoid micturition. Further conditions for the definition of OAB were no post void residual urine and a Bell shape curve in the uroflowmetry. The study was blinded for patients and parents as well as for the professionals who evaluated the outcome. All parents signed the agreement to participate in the study. This study was approved by our hospital ethical committee with a register as 12/06. A voiding diary was kept for 3 days as an assessment tool for evaluating all patients. Post void residual urine was evaluated by ultrasound and was considered abnormal when was higher than 10% of the expected bladder capacity in ml ((age +2) x 30)15 or when above 20 ml. Thirty-five patients had a post void residual urine less than 5 ml and three had between 5 and 20 ml. Exclusion criteria included the following conditions: patients with lower urinary symptoms that were secondary to anatomical anomalies such as posterior urethral valves, ureterocele or ectopic ureter; patients with neurogenic bladder; non-residency (children who lived outside of the city where the trial took place) and inability to comply with the treatment requirements. We used the following 5 criteria to evaluate the outcome in intent to treat analysis. 1) The parents were asked If their child symptomatically improved

significantly, mildly or not at all; 2) A visual analogical scale (VAS) from 0 to 10 was

used by the parents in which 0 meant no improvement and 10 meant complete resolution of symptoms; 3) Parents were asked to pick a number from 0 to 10 to rate the symptoms resolution (we multiplied this number by 10 to obtain a percentage); 4) A non - validated adapted Score of Toronto16 was used before and after treatment; 5) The numbers of voids a day, including mean and maximum bladder capacity before and after treatment, were evaluated in the voiding diary. All children underwent urotherapy. The training is presented in an attractive booklet containing demonstrative illustrations which re-enforce the necessity: 1) to void before sleeping, 2) to increase the volume of ingested liquid per day, 3) to eat foods rich in fiber, 4) to avoid the postponement of voiding when experiencing symptoms of urgency. The girls are asked to prioritize voiding comfort by avoiding sitting on a toilet seat with an overly large opening. The booklet suggests options of toilet seat adapters and foot supports to adjust for height problems. The booklet further recommends that at the moment of urination, the child should lightly flex his spine and relax the abdominal musculature. sleeping at the time of urination. PSTENS was administered in the office. Two superficial electrodes of 3.5 cm, placed on each side of S3 and S2. Electrodes were also placed in the scapular area 3 cm above the inferior scapular edge (fig.1). Electrical energy was produced by a generator (Dualpex Uro 961, Quark, Piracicaba-So Paulo, Brazil). The treatment consisted of 20 sessions of PSTENS. The frequency used was 10 Hz with a generated pulse of 700s. The intensity of the current was increased to the maximum level tolerated by the child. PSTENS was performed 3 times a week, with sessions of 20 min. The patients were reevaluated immediately after finishing the treatment. Patients from the sham group, who did not have a complete remission of symptoms, The booklet cites that the stomach should be

continued the procedure with 20 more sessions of PSTENS.

For these sessions

however, the stimulus was only applied in the lower sacral area and the sham group also became also the test group. The difference of the categorical variables was analyzed by chi-square test (2) or Fishers exact test. The pareated analysis was performed using pareated t Student test or Wilcoxon test. The Student t test or Mann-Whitney was used to compare independent variables. The level of statistical significance considered was below 5%.

Results

Thirty-seven children with symptoms of OAB were included in the study, 25 girls and 12 boys, with an average of age of 7.5 (2,8) years and a median age of 7 (510) years, were randomly assigned in 2 groups: 21 in the test and 16 in the sham group. Demographic and clinical characteristics of the groups are demonstrated in table 1. Female gender was predominant in both groups, 13 (61,9%) and 12 (75%) in test and control groups, respectively. The majority of the patients had both daytime and

nocturnal enuresis, presented holding maneuvers to avoid micturition and had a history of UTI. Information about maximum voiding volume (Max VV), mean voiding volume (MVV), and number of voids (NV) in the voiding diary, along with the values of the modified Toronto Score before and after treatment are demonstrated in the table 2. There was no statistical difference in the values between groups. A total of 37 children underwent to treatment, 21 in the test and 16 in the sham group. In the test group 2 children did not finish the treatment. One child left the group in the 8th session because of the mothers health problem. The other presented UTI in the 15th session and did not return to the treatment. Comparison of the results- Test versus sham group: The parents reported complete improvement of symptoms in 61.9% of the test group. There was no case of complete resolution of symptoms in the sham group (p<

0,001). Significant improvement of symptoms was found in 38.1% of the patients in the test group and in 31.3% in the sham group. This is demonstrated in table 3. The results according to AVS is demonstrated in figure 2. The lowest value found in the test group was 5 and in this group 13 parents marked the position of what was considered the highest therapeutical success. In the control group, the highest position marked was 9 (p=0.004). When the criteria for success was percentage of improvement of symptoms, the highest improvement was found in the test group (figure 3). In this group, 12 parents reported 100% improvement of symptoms while the lowest reported improvement was 50%. In the sham group, no parents reported 100% of improvement and 10 reported improvement of 40% or less. The values of the modified Toronto Score in the test and sham groups, before and after treatment, can be seen in figures 4 and 5, respectively. There was a

statistically significant difference in the values of the score before and after treatment in both groups, p < 0,001 e p = 0,008, respectively. However the score was reduced more significantly in the test group in comparison with the sham group, p = 0,011. The distribution of Max VV and MVV is demonstrated in figure 6. There was a significant increase in Max VV and in MVV in the test group in comparison with the sham group (p = 0,001 and p = 0,003, respectively). The NV before and after treatment is demonstrated in figure 7. There was a significant increase in NV in the test group in comparison with the sham group (p = 0,013). Figure 8 presents the Consort Fluxogram.

Results of the patients in the sham group who underwent PSTENS: Of the sixteen children in the sham group who underwent PSTENS, 14 finished all 20 sessions. In the case of one child who stopped in the 18th session, there was a reported 100% improvement. Another child who was not complaint since the beginning of the PSTENS, abandoned treatment in 14th session while reporting a 70% improvement of symptoms. In the end, 100% improvement was reported in 13 (81.3%), 90% in 1 (6.3%), 80% in another (6.3%) and finally, another child had a 70% improvement of symptoms (6.3%). Final results (all patients who underwent PSTENS): Six children maintained daytime incontinence after treatment. Two are on anticholinergics. After a mean follow up of 16.2 months (ranging from 3 to 29 months) recurrence of symptoms was seen in 4 children (10.8%). Three of them are on anticholinergics. Four children presented UTI. One was operated for grade IV vesicoureteral reflux; one had a 90% symptomatic improvement but eventually postponed micturition; one presented recurrence of OAB and UTI after a period of complete improvement of the symptoms; and one child presented UTI in the 15th session and abandoned the follow up.

Discussion We reported in this study that in the test group 61.9% of the patients showed complete improvement of symptoms and 38.1% of the cases showed a significant improvement of symptoms. However, in the sham group no patient had complete improvement and 31.3% presented some improvement of symptoms. When the sham group underwent PSTENS, complete improvement was reported in 81.3% of the cases and significant improvement was reported in the remaining cases. Thus, a complete improvement of symptoms was reported in 70.3% of all patients who underwent PSTENS. For all criteria for success that we employed in the study

(percentage of improvement, AVS and Toronto score), the test group compared favorably with the sham group. These positive results reaffirm our recently published data for a prospective case series in which 63% of the patients symptomatically improved completely and 20% improved significantly13. In another study of 49 children (30 with at least 2 years of follow up) we have demonstrated that for the long term, TENSPS is associated with complete resolution of the symptoms in 78% of the cases. The rate of recurrence after an initial complete remission of symptoms was 10%. To our knowledge this is the first study to show in a randomized clinical trial that electrical stimulation is effective in children with OAB. It is interesting that oxybutinin have been used for many years without the support of randomized studies. On the contrary, in a randomized double blind study, there was no difference between tolterodine and placebo in children with OAB10. In a systematic review of randomized clinical trials for OAB, there was no study that proves that any treatment is effective for OAB children9. However, in a recent randomized clinical trial tolterodine proved to be better than behavior modification plus placebo.17 The use of anticholinergics has

disadvantages. Compliance for children with a program of daily usage is difficult.10 It is not clear for how long the medication should be used. Also, the rate of side effects such as dry mouth, constipation, flushing and fever ranges in the area of 50%. For this reason, the medication is suspended in around 10% of the cases. 18,19 PSTENS for OAB was used initially in adults.20 Several authors described PSTENS in children with good results, but invasive techniques of electrical stimulation preclude its widespread usage in children.21-24. Hoebeke et al. and Bower et al. reported the first 2 series of PSTENS over S3 for children with OAB.
11,12

The treatment was

performed at home under parental supervision. Treatment was daily for 1-2 hours during a period of 5 to 6 months. In the Hoebeke et al. study, PSTENS was performed in 15 girls and 26 boys with OAB that did not respond to others kinds of treatment. One year after treatment the rate of complete resolution of symptoms was 51,2%11. Bower et al. treated with PSTENS or TENS over supra pubic area in 17 children, 15 girls and 2 boys. They used a frequency of 10Hz, with PSTENS lower sacral. The treatment was twice a day for a period of 1 to 5 months. Each session lasted one hour. They reported complete resolution of symptoms in 7 out of the 15 children with daytime incontinence.12 We were the first to describe the ambulatory, short term PSTENS in children. 13 In this treatment PSTENS is performed for 20 minutes, 3 times a week, for a maximum of 20 sessions. The frequency is 10 Hz. We believe that with a lower number of sessions the compliance with the treatment may be higher while helping the diffusion of the method. Moreover, when the treatment performed by a professional, the current intensity until the sensitivity threshold can be reached. This is seldom possible when performed by the patient. We use the frequency of 10 Hz, which according to

Lindstrom et al, causes better bladder inhibition in cats. 25 Also, this frequency has been widely successful in adult cases. 26 The mechanics of the electrical stimulation for OAB is far from being established. It is known that it not only acts directly on the muscle fibers but also on the reflexes.27,28 The activation of the inhibitory sympathetic neurons and the inhibition of parasympathetic excitatory neurons that go to the bladder may play a role in the action mechanism of the electrical stimulation.29 These reflexogenic pathways were described in intra vaginal electrical stimulation in animals.30,31 It has been also proposed that the pudendal nerve could be activated. This consequently would relax the bladder and inhibit detrusor over activity by external urethral sphincter contraction or by inhibition of interneurons.32 However, a supraspinal effect of the electrical stimulation has been reported. Liao et al. investigated whether brain reorganization occurred along with clinical improvement after sacral-root stimulation.33 Six patients, 33 to 68 years old, with idiopathic OAB were included in the study. All demonstrated clinical

improvement after sacral-root stimulation. Transcranial magnetic stimulation was applied to study motor cortex excitability and the brain mapping of the muscle. Motor cortex excitability and the area of representation for the flexor hallucis brevis muscle increased for at least 30 min after sacral-root stimulation had terminated. These results showed that sustained sacral-root stimulation may reorganize the human brain and its ability to excite the motor cortex, in turn modulating the lower urinary tract function. Because all patients were treated by urotherapy, we did not know the results of PSTENS where this treatment had not taken place. We therefore recommend that urotherapy must be performed concomitantly. Since no patient had complete resolution of symptoms in the sham group (low response rate associated with urotherapy only), in

our department, children with OAB are treated primarily with PSTENS associated to urotherapy. The present study demonstrated that after PSTENS there was an increase in the maximum and medium voiding volume as well a reduction in the number of voids per day. This increase was statistically higher than in the sham group. This confirms the findings of other authors.34,35 It was also evident that there is a larger reduction in the Toronto score for the test group in comparison with the sham group. Our study is limited by the unavoidable professional / patient interaction in the sham group. The follow up is short, however our long term study shows evidence that the positive outcome is sustained over with time.14 Future steps regarding PSTENS research include the investigation of the effectiveness of a lower number of sessions a week, alternative pulse width, frequency and the addition of more sessions for patients who do not show complete improvement by the 20th session.

CONCLUSIONS

PSTENS is effective for treating OAB in children in a randomized clinical trial. There was a higher improvement of symptoms, increase in the bladder capacity and reduction of the number of voids in patients who underwent PSTENS in comparison with sham group.

References

1- Nevus T, von Gontard A, Hoebeke P et al: The standardization of terminology of lower urinary tract function in children and adolescents: report from the Standardisation Committee of the International Children's Continence Society.J Urol 2006;176:314. 2- Hellstrm AL, Hanson E, Hansson S et al: Micturition habits and incontinence in 7-year-old Swedish school entrants. Eur J Pediatr 1990; 149:434. 3- von Gontard A, Lettgen B, Olbing H et al: Behavioural problems in children with urge incontinence and voiding postponement: a comparison of a paediatric and child psychiatric sample. Br J Urol 1998; 81:100. 4- Hgglf B, Andrn O, Bergstrm E et al: Self-esteem in children with nocturnal enuresis and urinary incontinence: improvement of self-esteem after treatment Eur Urol 1998; 33:16. 5- Barroso U Jr, Barroso DV, Jacobino M et al: Etiology of urinary tract infection in scholar children. Int Braz J Urol 2003; 29:450. 6- Barroso U Jr, Jednak R, Barthold JS, Gonzlez R: Outcome of ureteral reimplantation in children with the urge syndrome. J Urol 2001; 166:1031. 7- Varlam DE, Dippell J: Non-neurogenic bladder and chronic renal insufficiency in childhood. Pediatr Nephrol 1995; 9:1. 8- Naseer SR, Steinhardt GF: New renal scars in children with urinary tract infections, vesicoureteral reflux and voiding dysfunction: a prospective evaluation. J Urol 1997; 158:566.

9- Sureshkumar P, Bower W, Craig JC, Knight JF: Treatment of daytime urinary incontinence in children: a systematic review of randomized controlled trials. J Urol 2003; 170:196. 10- Nijman RJ, Borgstein NG, Ellsworth P, Djurhuus JC: Tolterodine treatment for children with symptoms of urinary urge incontinence suggestive of detrusor overactivity: results from 2 randomized, placebo controlled trials. J Urol 2005; 173:1334. 11- Hoebeke P, Van Laecke E, Everaert K et al: Transcutaneous neuromodulation for the urge syndrome in children: a pilot study. J Urol 2001; 166:2416. 12- Bower WF, Moore KH, Adams RD:A pilot study of the home application of transcutaneous neuromodulation in children with urgency or urge incontinence. J Urol 2001; 166:2420. 13- Barroso U Jr, Lordlo P, Lopes AA et al: Nonpharmacological treatment of lower urinary tract dysfunction using biofeedback and transcutaneous electrical stimulation: a pilot study. BJU Int 2006; 98:166. 14- Lordlo P, Soares PVL, Maciel I et al: Prospective study of transcutaneous parasacral electrical stimulation for Overactive bladder in children: Long term results. J Urol, in press 15- Berger RM, Maizels M, Moran GC et al: Bladder capacity (ounces) equals age (years) plus 2 predicts normal bladder capacity and aids in diagnosis of abnormal voiding patterns. J Urol 1983; 129:347. 16- Farhat W, Bgli DJ, Capolicchio G et al.: The dysfunctional voiding scoring system: quantitative standardization of dysfunctional voiding symptoms in children. J Urol 2000; 164:1011

17- Ayan S, Topsakal K, Gokce G, Gultekin EY: Efficacy of combined anticholinergic treatment and behavioral modification as a first line treatment for nonneurogenic and nonanatomical voiding dysfunction in children: a randomized controlled trial. J Urol 2007; 177:2325. 18- Youdim, K., Kogan, BA: Prelimiraty study of the safety and efficacy of extended-release oxybutynin in children. Urology 2002; 59:428. 19- Nijman, RJ: Role of antimuscarinics in the treatment of nonneurogenic daytime urinary incontinence in children Urology 2004; 63:45. 20- Moore T, Schofield PF: Treatment of stress incontinence by maximum perineal electrical stimulation. Br Med J 1967; 3:150. 21- Gladh G, Mattsson S, Lindstrm S: Anogenital electrical stimulation as treatment of urge incontinence in children. BJU Int 2001; 87:366. 22- Pugach JL, Salvin L, Steinhardt GF. Intravesical electrostimulation in pediatric patients with spinal cord defects. J Urol 2000; 164:965. 23- De Gennaro M, Capitanucci ML, Mastracci P et al: Percutaneous tibial nerve neuromodulation is well tolerated in children and effective for treating refractory vesical dysfunction. J Urol 2004; 171:1911. 24- Hoebeke P, Renson C, Petillon L et al: Percutaneous electrical nerve stimulation in children with therapy resistant nonneuropathic bladder sphincter dysfunction: a pilot study. J Urol 2002; 168:2605. 25- Lindstrm S, Fall M, Carlsson CA, Erlandson BE: The neurophysiological basis of bladder inhibition in response to intravaginal electrical stimulation. J Urol 1983; 129:405.

26- Ohlsson BL, Fall M, Frankenberg-Sommar S: Effects of external and direct pudendal nerve maximal electrical stimulation in the treatment of the uninhibited overactive bladder. Br J Urol 1989; 64:374. 27- Trontelj JV, Janko M, Godec C et al: Proceedings: Electrical stimulation for urinary incontinence: a neurophysiological study.Urol Int 1974; 29:213. 28- Godec C, Cass AS, Ayala GF: Bladder inhibition with functional electrical stimulation. Urology 1975; 6:663. 29- Fall M, Erlandson BE, Carlsson CA, Lindstrm S.The effect of intravanginal electrical stimulation on the feline urethra and urinary bladder. Neuronal mechanisms. Scand J Urol Nephrol Suppl 1977; 44:19. 30- Sundin T, Carlsson CA: Reconstruction of severed dorsal roots innervating the urinary bladder. An experimental study in cats. I. Studies on the normal afferent pathways in the pelvic and pudendal nerves. Scand J Urol Nephrol 1972; 6:176. 31- Sundin T, Carlsson CA, Kock NG: Detrusor inhibition induced from mechanical stimulation of the anal region and from electrical stimulation of pudendal nerve afferents. An experimental study in cats. Invest Urol 1974; 11:374. 32- Franco I. Overactive bladder in children. Part 1: Pathophysiology. J Urol 2007; 178:761. 33- Liao KK, Chen JT, Lai KL, Liu CY, Lin CY, Lin YY, Yu BK, Wu ZA: Effect of sacral-root stimulation on the motor cortex in patients with idiopathic overactive bladder syndrome. Neurophysiol Clin 2008; 38:39. 34- Petersen T, Just-Christensen JE, Kousgaard P, Holmboe B, Klemar B: Anal sphincter maximum functional electrical stimulation in detrusor hyperreflexia. J Urol 1994; 152:1460.

35- Zllner-Nielsen M, Samuelsson SM: Maximal electrical stimulation of patients with frequency, urgency and urge incontinence. Report of 38 cases. Acta Obstet Gynecol Scand 1992; 71:629.

*Key of Definitions for Abbreviations (only include abbreviations used 3 times or more in manuscript)

Lower urinary tract dysfunction: LUTD Overactive bladder: OAB Urinary tract infection: UTI Para sacral transcutaneous electrical neural stimulation: PSTENS Visual analogical scale: VAS Maximum voiding volume: Max VV Mean voiding volume: MVV Number of voids: NV

Table

Table 1 Distribution of demographic and clinical data between groups Variable Test Group N= 21 (%) Mean age SD Female gender Daytime incontinence Holding maneuvers Nocturnal enuresis UTI Pyelonephritis 7,5 ( 3) 13 (61,9) 16 (76,2) 15 (71,4) 16 (76,2) 13 (61,9) 8 (38,1) Sham Group N=16 (%) 7,4 ( 2,8) 12 (75) 14 (87,5) 12 (75) 13 (81,3) 11 (68,8) 7 (43,8)

n = number of patients; SD= standard deviation; UTI = urinary tract infection.

Table 2 Data from the voiding diary and Modified Toronto Score between groups. Variables Test Group N=21 Max VV (ml). Median (IQ) MVV (ml). Median (IQ) NV. Median (IQ) Score of Toronto. Mean SD 150 (117 - 200) 87,5 (45,2 107,4) 7 (5,5 9,5) 9,6 ( 5,2) Sham Group N=16 140 (110 207,5) 76,9 (59,7 88,8) 7,2 (6,2 8,6) 10,8 ( 5,6)

n = number of patients; Max VV = maximum voiding volume; MVV = mean voiding volume; NV= number of voids; SD = standard deviation; IQ = interquatil interval.

Table 3 Results according to the improvement of the symptoms Complete n (%) Test group Sham group 13 (61,9) 0 (0) Significant n (%) 8 (38,1) 5 (31,3) Mild n (%) 0 (0) 7 (43,8) No improvement n (%) 0 (0) 4 (25)

n = number of patients; p < 0,001

Figure

Figure 1 . Position of the superficial electrodes in the scapular and lower sacral regions during the application of electrical stimulation.

Participating Group

14

Test Control

12

Number of Cases
10

p = 0,002

0 1 2 3 4 5 7 8 9 10

Values in relation to the positions marked in the VAS

Figure 2: Distribution of values encountered in the VAS for the test and control groups

12

Participating Group
Test Control

Number of children
10

p = 0,004
4 2

0 10 20 30 40 50 60 70 80 85 90 95 100

Values marked by parent or guardian in percent(%) in reference to therapeutical success in the test and control groups

Figure 3: Distribution of values in percent marked by parent or guardian

p < 0,001

Figure 4: Modified Toronto score before and after treatment in the test group

p = 0,008

Figure 5: Modified Toronto score before and after treatment in the sham group

VMMax pre-treatment VMMax post treatment

300

Test group

p = 0,001

Sham group p = 0,249

200

100

Test

Control Group which participated

Figure 6: Max VV and MVV before and after treatment between groups.

25 18

Pre treatment miccional frequency

Post treatment miccional frequency

20

15

10

Test Group
10

p = 0,013

Control Group p = 0,105

Test

Control Group that participated

Figure 7: NV before and after treatment.

Figure 8: CONSORT Fluxogram

Assessed for Eligibility (n=37)

Enrollment

Excluded

(n = 0)

Randomized

(n = 37)

Allocation

Allocated in test group (n = 21)

Allocated in control group (n = 16)

Follow-up

Discontinued intervention (n = 2) Reasons: 1 Mothers health problem 2 Gave up treatment after UTI

Discontinued intervention (n = 0)

Analysis

Analyzed (n= 21)

Analyzed (n= 16)

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