Refractory Monosymptomatic Nocturnal Enuresis Treatment

Refractory Monosymptomatic Nocturnal Enuresis Treatment Role of Posterior Tibial Nerve Stimulation in the Treatment of  Refractory Monosymptomatic Nocturnal Enuresis: A Pilot Study Ali Abdel Raheem,* Yasser Farahat, Osama El-Gamal, Maged Ragab,  Mohamed Radwan, Abdel Hamid El-Bahnasy, Abdel Naser El-Gamasy  and Mohamed Rasheed Purpose: We evaluated the early clinical and urodynamic results of posterior tibial  nerve stimulation in patients with refractory monosymptomatic nocturnal enuresis. Materials and Methods: We randomly assigned 28 patients with refractory  monosymptomatic nocturnal enuresis to 2 equal groups. Group 1 received a  weekly session of posterior tibial nerve stimulation for 12 weeks and group 2 was  the placebo group. Evaluation was performed in each group at baseline and after  posterior tibial nerve stimulation to compare clinical and urodynamic findings. Another clinical assessment was done 3 months after the first followup. Results: The 2 groups were comparable in baseline clinical and urodynamic data. Overall, 13 patients (46.4%) had detrusor overactivity and 14 (50%) had decreased  bladder capacity. After treatment 11 group 1 patients (78.6%) had a partial or full  response to posterior tibial nerve stimulation but only 2 (14.3%) in group 2 had a  partial response (p 0.002). Also, the average number of wet nights in group 1 was  significantly lower than at baseline (p 0.002). All urodynamic parameters significantly  improved in group 1. In contrast, the number of wet nights and urodynamic  parameters did not change significantly in group 2. At 3-month followup the number  of patients with a partial or full response in group 1 had decreased from 11 (78.6%)  to 6 (42.9%). No change was evident in group 2. Conclusions: Posterior tibial nerve stimulation can be a viable treatment option  in some patients with refractory monosymptomatic nocturnal enuresis. However,  deterioration in some responders with time suggests the need for maintenance  protocols. Key Words: urinary bladder, nocturnal enuresis, transcutaneous electric  nerve stimulation, urodynamics, treatment outcome  NOCTURNAL enuresis is usually associated  with severe psychological and social  distress to children and their families. 1 In recent years several treatment  modalities emerged to treat NE, such  as behavioral therapy,2 alarm treatment,  3 medical therapy with desmopressin,  oxybutynin and imipramine,  and combination therapy.4–6 However,  none has been completely successful and  the relapse rate of all of them is significant. 7–9 Therefore, there is a great need  to find other treatments that could be  more effective and durable than current  therapy.  The pathogenesis of refractory NE  was discussed in many studies and attributed  to decreased bladder capacity  and/or PTNS was introduced with early  promising results as neuromodulative  therapy for diseases that involve the  lower urinary tract and for refractory conditions in  adults and children.15–19 These beneficial effects of  PTNS for controlling various bladder disorders led  us to try it in patients with refractory primary MNE.   MATERIALS AND METHODS A total of 28 patients were included in this prospective,  randomized, placebo controlled, single blind study from  January 2010 to March 2012 at the urology department at  Tanta University Hospital. The study protocol was reviewed  and approved by the Tanta University institutional  review board. Informed consent was obtained from  all participants or from parents if the patient was younger  than 18 years. We recruited patients with severe (3 or more wet nights  per week) primary MNE at least 6 months in duration in  whom available conventional and combination therapies  had failed, including desmopressin, anticholinergics and  an alarm. We excluded those with secondary NE, nonMNE,  nocturnal polyuria and any neurological abnormality. All patients provided a detailed history and underwent  complete physical examination, urinalysis, x-ray of the  lumbo-sacral spine and ultrasound of the urinary system.   All patients were asked to keep a nocturnal enuresis diary  for 2 weeks, which included the time of sleep and arousal,  and whether they had a dry or wet bed in the morning. Nocturnal urinary output was measured as the total urine  volume collected in the diaper after voiding during the last  night (assessed by weighing the diaper in the morning)  plus the first morning urine volume. Nocturnal polyuria  was defined as nocturnal urine output 130% or greater of   EBC for age.20 The Arabic version of a 2-day frequency-volume chart  (adapted from the Pan Arab Continence Society, www.pacsoffice.com) was obtained from all patients to confirm  that the problem was MNE. Daytime functional bladder capacity was considered the recorded MVV. EBC for age  was calculated by the formula, 30 _ (age in years _ 30). Children with MVV less than 65% of EBC for age were  considered to have a small bladder.20 All patients also underwent urodynamic tests, as performed  by the same urodynamicist using a Delphis-KT  device (Laborie, Toronto, Ontario, Canada), including  1) uroflowmetry with PVR estimation by ultrasound for at  least 2 voids and 2) cystometrogram, including 1 filling  cycle using an 8Fr double lumen urethral catheter with  the patient supine and a slow filling rate of 10 ml per  minute. Patients were randomly divided into 2 equal groups by  method. Randomization was done blindly by having an  independent nurse randomly take a card from an envelope  containing 14 cards for group 1 and 14 for group 2. Group  1 received active PTNS treatment sessions using the  Urgent ® PC Neuromodulation System, while group 2 underwent  a sham procedure. Treatment Protocol We applied the technique described by Stoller.21 The patient  lay supine with the soles of the feet together, and the  knees abducted and flexed (frog position). A 34 gauge  needle was inserted percutaneously approximately 2  inches (5 cm) cephalad to the medial malleolus and 1 cm  from the posterior margin of the tibia at an angle of 60  degrees from the skin surface and the lead wire attached  to it. The surface electrode was placed on the same leg  near the arch of the foot over the calcaneus bone. The  device was turned on and amplitude was slowly increased  until the largest toe of the patient began to curl, the digits  fanned or the entire foot extended, indicating proximity to  the nerve bundle (see figure). If this response was not  achieved or pain occurred near the insertion site, the  device was turned off and the procedure was repeated. When the needle was inserted in the correct position, the  current was set at a tolerable level (pain threshold) and  the session continued for 30 minutes. For the sham procedure we tested only the foot response  to the electrical impulse and then turned off the  apparatus during the whole session. To avoid patient  identification of the type of procedure all participants  were informed that they may or may not feel a sensory  stimulus in the lower extremities during the treatment  sessions. Groups 1 and 2 underwent 12 weekly outpatient treatment  sessions. All participants were advised to stop all  medical treatment for NE at least 1 month before starting  PTNS but to continue behavioral therapy, including fluid  A, neuromodulation system. B, system in use with flexion of left largest toe.   restriction at night, complete bladder emptying before  sleep and awakening 2 hours after sleep to void. Patient Assessment The first patient evaluation was done in the first 2 weeks  after the last session. This evaluation involved repeating  the clinical and urodynamic assessments. The clinical part  included a nocturnal enuresis diary for 2 weeks in which  the number of wet nights/week was reported as well as a  2-day frequency-volume chart. The clinical response to treatment was assessed as  outlined by the International Children’s Continence Society,  including no response—less than a 50% decrease in  the total number of wet nights, partial response—50% to  89% decrease, response—90% or greater decrease and full  response—100% decrease.20 Urodynamic assessment included  uroflowmetry, PVR measurement and cystometry. The second evaluation was done 3 months after the last  session. It involved clinical evaluation using nocturnal  and voiding diaries only. Statistical Analysis All statistical analysis was performed using SPSS ® 17.   Data are shown as the mean SD unless otherwise specified. The Student t and paired sample t tests were used  for comparison between groups and in the same group,  respectively. Nonparametric data were compared by the  Wilcoxon signed ranks or Mann-Whitney U test. Statistical  significance was considered at p 0.05. RESULTS Recruited for this study were 28 patients with refractory  NE who met inclusion criteria. Initial assessment  and baseline characteristics of each group  showed no significant difference in clinical and urodynamic  parameters (table 1). Overall, in the 2  groups DO was present in 13 patients (46.4%) and  14 (50%) had decreased bladder capacity.   The procedure was performed easily with no adverse  effects in all cases. No patient discontinued  the planned sessions. At the end of the PTNS sessions clinical assessment  revealed significant improvement in the average number  of wet nights per week in group 1 (decrease from  4.7 to 2.6, p 0.002, table 2). Compared to the placebo  group, the number of wet nights after treatment was  significantly lower in group 1 (p 0.041, table 2). At  that time 4 group 1 patients (28.6%) had a complete  response to PTNS, 7 (50%) had a partial response and  3 were nonresponders. However, in group 2 there were  2 patients (14.3%) with a partial response, while the  remainder did not respond. When we compared the 2  groups, the difference in this response rate was statistically  significant (p 0.002, table 2). At first evaluation after the end of treatment, the  active group showed significant improvement in all  urodynamic parameters compared to baseline, including  first and strong desire to void, and MCC  (p 0.002, 0.01 and 0.000, respectively, table 2). In  group 2 these parameters did not significantly differ  compared to baseline (table 2). Also, DO disappeared  in 2 of 7 group 1 patients but this improvement was  not noted in the sham treated group (table 2). Statistical  analysis revealed that the difference be- Table 1. Patient characteristics Active Placebo p Value No. boys/girls 8/6 9/5 1 Mean SD age (yrs) 13.7 2.8 14 2.8 0.8 Mean SD body mass index (kg/m2) 24.95 4.40 26.27 4.23 0.43 Mean SD max urine flow (ml/sec) 26.85 6.74 23.28 5.49 0.13 Mean SD PVR (ml) 6.21 7.11 5.86 5.48 0.9 Mean SD daytime frequency 3.9 0.67 4.29 0.64 0.07 Mean SD MVV (ml) 266.57 82 288.93 106.29 0.27 Mean SD No. wet nights/wk 4.7 1.3 5.1 1.4 0.42 No. detrusor overactivity: Present 7 6 1 Absent 7 8 — Mean SD void desire (ml): 1st 148.46 25.89 153.50 21.65 0.59 Strong 260.43 84.18 271.79 75.43 0.71 Mean SD MCC (ml) 291.21 86.82 322.21 76.04 0.32 Table 2. Intragroup and intergroup comparisons of clinical and urodynamic findings after PTNS at first evaluation Active Placebo Baseline After Treatment p Value Baseline After Treatment p Value Posttreatment p Value Mean SD void desire (ml): 1st 148.46 25.89 177.71 35.48 0.002 153.50 21.65 154.14 20.71 0.59 0.041 Strong 260.43 84.18 283.64 72.03 0.01 271.79 75.43 271.6 72.8 0.94 0.67 Mean SD MCC (ml) 291.21 86.82 322.5 65.89 0.000 322.21 76.04 323.57 77.44 0.57 0.97 No. detrusor overactivity: Present 7 5 0.44 6 6 1 0.7 Absent 7 9 8 8 Mean SD MVV (ml) 266.57 82 280.14 71.81 0.022 288.93 106.29 291.07 96.84 0.73 0.6 Mean SD No. wet nights/wk 4.7 1.3 2.6 2.2 0.002 5.1 1.4 4.7 2.1 0.08 0.041 No. response: — — — — Full 4 0 0.002 Partial 7 2 None 3 12 1516 POSTERIOR TIBIAL NERVE STIMULATION FOR REFRACTORY NOCTURNAL ENURESIS tween the 2 groups in this regard was not statistically  significant (p 0.7, table 2). Furthermore, in  this evaluation urodynamic parameters showed that  bladder volume at first desire to void was significantly  higher in group 1 than in group 2 (p 0.041). On the other hand, bladder volume at strong desire  to void and MCC did not significantly differ between  the groups (p 0.67 and 0.97, respectively, table 2). Five of the 8 group 1 patients with decreased EBC  showed improved capacity. MVV also significantly  increased after treatment from a mean of 266.57  82 to 280.14 71.81 cc (p 0.022, table 2). When we studied the relationship between the response  to PTNS and initial urodynamic findings, we  noted that all 10 group 1 patients with small bladder  capacity and/or DO showed a good response to treatment,  including 4 and 6 with a full and partial response,  respectively. However, when we compared the type of  response in those with normal vs abnormal urodynamic  results, the 4 patients with normal urodynamic findings  in this group had a poor response to the sessions, including  3 with no response and 1 with only a partial response. This difference was significant (p 0.007). Clinical results at 3 months after the last session  showed some deterioration in early results in the  active group. In this group the number of patients     ith a full response decreased from 4 to 2 and the  number of those with a partial response decreased  from 7 to 4. No change was detected in the other  group. However, when we compared the response  rate in the 2 groups at this time, we detected no  significant difference (p 0.13). In addition, the  average number of wet nights per week at that time  was 2.9 in group 1 and 4.2 in group 2, which did not  significantly differ (p 0.07). DISCUSSION This study demonstrates that PTNS could be of value  in some patients with primaryMNEin whom previous  conventional therapies failed. To our knowledge this  treatment modality has not been tried before in such  cases but it has been successfully used for overactive  bladder syndrome,22,23 lower urinary tract dysfunction  in adults and children,15,18 refractory overactive bladder,  16 refractory vesical dysfunction19 and refractory  nonneurogenic bladder sphincter dysfunction.17   Absent daytime lower urinary tract symptoms in  patients with NE does not necessarily mean that the  bladder functions well because DO and/or decreased  bladder capacity was previously reported in such  patients.10,11 The clinical response to desmopressin  therapy is less satisfactory when NE is associated  with decreased bladder capacity and/or DO.12–14 In  our study we detected DO and decreased bladder  capacity in 46.4% and 50% of patients, respectively,  although patients with MNE only were included in  analysis. These values agree with previous reports  showing bladder overactivity24 and small bladder  capacity25 in 49% and 50% of children with MNE,  respectively. These findings may partially explain  the mechanism of resistance to the previous treatment  trials in our patients. Our results and those of others reveal that PTNS  can be applied easily and safely in children.18,19  After the 12 PTNS sessions in our series, patients  showed a significant increase in MVV and urodynamic  parameters, including first and strong desire  to void, and MCC, compared to the placebo group. These results agree with those in previous reports  demonstrating that PTNS increased cystometric capacity  from 197 to 252 cc26 and from 243 to 340 cc,27  and increased MVV by 39 cc, which was statistically  significant.23 However, at 3-month followup we detected some  deterioration in the response rate compared to early  results. The overall number of full and partial responders  decreased from 11 (78.6%) to 6 (42.9%) in  group 1. This deterioration during followup suggests  that PTNS may have temporary efficacy and its effect  decreases gradually with time. This finding was also  noted in patients with overactive bladder treated with  PTNS. van der Pal reported that 7 of 11 patients with  an initially good response had evidence of subjective  and objective deterioration after PTNS.28 They suggested  the need for maintenance treatment. The early promising results of this study encouraged  us to suggest that PTNS might be effective  in patients with refractory primary MNE in  whom nocturnal polyuria is not an etiological factor  but in whom the main underlying pathological  condition is decreased bladder capacity and/or DO. However, the exact mechanism that could explain  the mode of action of this treatment modality is  still unknown. PTNS may induce some inhibitory  effects on DO. The existence of this functional  abnormality in the bladder implies that the detrusor  is not completely relaxed between voids.   Therefore, the capacity of the overactive bladder is  usually smaller than that of the bladder with a  normal detrusor. Consequently, the clinical response  usually occurs when bladder capacity increases  and DO improves after PTNS. This explanation  may be supported by the improvement in  bladder capacity (functional and cystometric) and  the disappearance of DO in patients who responded  to PTNS in our study. The main limitations of this study are the small  sample size and the short 3-month followup. In  addition, we did not repeat urodynamic tests at  the second followup at 3 months to avoid patient  discomfort but depended only on the patient clinical  response. However, this information could be important for assessing the cause of the deterioration in PTNS efficacy after treatment was  stopped. CONCLUSIONS PTNS appears to be a viable treatment option in  some patients with refractory primary MNE. However,  deterioration in the response rate with time  raises important questions about the long-term  efficacy of this therapy and the need for further  maintenance sessions. More studies are needed to  support our findings and select patients who  would be good candidates for this therapy.