Sensibility of Children of Different Age Groups to Alarm Intervention for Enuresis

Address for correspondence: KV Kosilov, MD, PhD Address: Ajax 10, corp.F, office 733, Vladivostok, Primorsky region, Russian Federation, RUVVO E-mail: address: oton2000@mail.ru Tel No: 7-914-717-3915; 7-423-231-2169 1Kirill Vladimirovich Kosilov, MD, PhD, Professor of Department of Social Sciences, School of Humanities, Far Eastern Federal University, Vladivostok, Primorsky region, Russian Federation, 2Sergay Alexandrovich Loparev, MD, urologist Department of Urology, City polyclinic No 3, Vladivostok, RF, 3Marina Anatolievna Ivanovskaya, MD, PhD, Associate Professor, Department of Law, Far Eastern Fisheries University, Vladivostok, RF, 4Liliya Viktorovna Kosilova, MD, doctor in the department of functional diagnostics, Med. association No 2 of Vladivostok-sity, Vladivostok, RF. This study was done at the Far Eastern Federal University, School of Humanities, Ajax 10, corp. F, office 733, Vladivostok, Primorsky region, Russian Federation, Tel./fax 7-(4232) 457-693, Website: www.dvfu.ru. Abstract


Introduction
P revalence of primary monosymptoma c night enuresis (PMNE) is high all over the world.According to various es ma ons, it varies from 4.7 to 12 % or even more.Age, gender and race of pa ents, as well as diagnos cs criteria used by the researchers, have an impact on the data on enuresis prevalence 1,2,3,4,5 .In 2012 Interna onal Children's Con nence Society (ICCS) and Na onal Clinical Guideline Centre, UK (NCGC) announced the rules and guidelines specifying several factors that can act as releaser of enuresis.They include change in an diure c hormone level, disturbance of sleep and sleep-wake cycle, delayed forma on of nerve refl ex mechanisms of awakening skill and some others 6,7 .
Therapeu c procedures for PMNE are also s pulated in ICCS rules.They point out to the use of the Alarm interven on and synthe c analog of an diure c hormone as fi rst-line therapy methods 8,9 .
Alarm interven on has been used for enuresis treatment for several decades 10,11,12 .However, the problem of eff ec veness of such therapy in age aspect appears to be insuffi ciently studied 13,14,15,16 .Meanwhile, it is known that percep on of extrinsic s mulates, reac ons of involuntary nervous system, resistance of uncondi oned nervous refl exes can be quite diff erent among children of various age and teenagers 17,18,19 .Hence, the purpose of this study is to try to fi nd out the diff erence in effi ciency of the Alarm interven on for children of diff erent age for improving recommenda ons on usage of alarm systems.

Material and Methods
Sampling consisted of 399 persons: 238 males and 161 females suff ering PMNE.Method of random numbers was used for group randomiza on.Sample size was calculated, using the formula for comparing two mean values and searching for correla ons, with refer to the percentage of response and monitoring losses: n= [A+B] 2 *2*SD 2 /DIFF2, where n is a sample size for each group, SD is standard devia on for primary outcome variable, DIFF is clinically signifi cant eff ect, А is signifi cance level that is taken as 5% and B is capacity that is taken at 80% in this case.
A method of random numbers was used for group randomiza on.Persons of both genders at the age of 7 -15 years old having at least two episodes of nocturnal enuresis per week were included into the treatment group.Then they were distributed into three age subgroups: А (7-9 years old; n=142), В (10-12 years old; n=130), C (13-15 years old, n=127).Persons with any chronic condi ons of visceral organs in the exacerba on phase, symptoms of detrusor dysfunc on, changed level of an diure c hormone and ear disorders were excluded from the group.
In the beginning of examina on all the pa ents, their parents or trustees fi lled in ques onnaire OAB-q SF 20,21 , while children and teenagers had urofl owmetry tests as well as laboratory tests, including tests for infl amma on and determina on of an diure c hormone level.Treatment control was carried out with the help of bladder diaries where episodes of nocturnal, spontaneous awakenings in case of desire to urinate, dry nights were registered 22 .Examina on, treatment and observa on scheme are shown in Fig. 1.Study checkpoints 1 and 2 are state of enuresis markers right a er treatment and within two months a er its end.
Alarm interven on was conducted by standard method with the use of device Wet Stop/ BYE-WET by PALCO LABS, Inc (USA).The Protocol of this randomized controlled study was performed in accordance with Good Clinical Prac ce (GCP), the Declara on of Helsinki and ICCS.
Ini al data were collected by applica on so ware Excel from standard Microso -ХР package and analyzed by JMP SAS Sta s cal Discovery 8.0.2 (SAS Ins tute, Cary, NC, USA).Wilcoxon criterion was used for comparison of the results in each group.One-way analysis of variance (ANOVAs) with Tukey and Kramer criterion was used for comparison of the eff ects in three age subgroups, processes con ngency was studied, using Spearman criterion.
Ethics commi ee approval was received for this study from the ethics commi ee of the Far Eastern Federal University on February 19, 2013.

Results
As result of processing ques onnaire OAB-q data collected in the beginning of study it was found out that median values of score for pa ents of the Groups А, B and C were 3.6 (1.1), 2.1 (1.5) and С -3.3 (1.2) respec vely.
Average value of an diure c hormone was 4.2 (1.1) nanogram/liter, and it corresponded to the standard values at certain level of osmolarity for each pa ent.Blood and urine tests did not reveal the signs of infl amma on process; the markers of helminthes infec on were not detected.
Table 1 shows the changes in frequency of enuresis episodes, spontaneous awakenings and number of dry nights in the beginning of study right a er the end of its ac ve phase and in two months a er the end of alarm systems usage.
Signifi cant decrease in the number of dry nights a er treatment was reported in junior and average age groups, yet in two months a er the end of the Alarm interven on only the varia ons from ini al values of pa ents of older group proved to be signifi cant.Comparison of fi nal values of this parameter between the groups allows to conform the signifi cance of diff erences between the Group В on the one hand and Groups А and С -on the other hand (p≤0.05 in both cases).
Right a er the end of treatment, the reduc on in number of episodes of enuresis was reported in junior and average age groups, while the fi nal values proved to be signifi cantly diff erent from ini al ones in Groups В (4.6 (0.9) → 2.6 (0.6), p≤0.05) and С ( 4.8 (0.8) →2.9 (0.6), p≤0.05).Signifi cant diff erence between ini al and fi nal values of parameter "spontaneous awakening episodes" was reported for the pa ents of junior and average age groups.Final values of the parameter in the Group В are signifi cantly higher than those in other groups (p≤0.05).Final numbers episodes of enuresis in Groups B and C are not signifi cantly diff erent among each other and are signifi cantly lower than in junior group.The curves refl ec ng changes in the number of cases of nocturnal urina on are almost synchronous for Groups В and С (r=0.83,p≤0.01) and moderately conjugate between the Group А on the one hand and Groups В and С -on the other hand (А-В: r=0.49, p≤0.05;A-C: r=0.57, p≤0.05).Correla on between the curves demonstra ng the changes in the number of episodes of nocturnal urina on i was also quite high (В-С: r=0.90 p≤0.01;А-C: r=0.59 p≤0.05;А-В: r=0.64 p≤0.05).
In junior age group the average number of alarm system actua ons prior to the appearance of the fi rst spontaneous awakening in case of desire to urinate was 6.8 (1.9), while the same parameter for the children of average and older age groups proved to be equal to 8.7 (4.1) and 12.2 (5.8) respec vely.Fig. 4 shows the change in the number of pa ents (in percentage points) who suff ered from PMNE during the whole monitoring period.As graphs suggest, the most posi ve result of Alarm-therapy has been reported in the Group В.In this group, not only was the percentage of children who suff er from PMNE right a er the treatment the lowest one, but also the result turned out to be the most stable one among all three groups.When carrying out study in 2 months a er the end of ac ve phase of the experiment, the percentage of children who suff ered from enuresis symptoms did not signifi cantly change (25.2% →28.5%, p≥0.5).Decent ini al result was achieved in the group of younger children too (А).The percentage of pa ents who turned out to be resistant to the Alarm-therapy was 31.1%,yet as early as in two months their propor on reached 57.4%, i.e. nocturnal urina on episodes of more than twice a week were reported for almost one child in two.Finally, in the group of older children, therapy course turned to be the least eff ec ve.The percentage of children who suff ered PMNE right a er its end and in two months a er were 48.5% and 51.3% respec vely.Thus, the eff ec veness of the Alarm-therapy in the group of teenagers of 12 to 14 has turned out to be the highest, with its result being the most stable one among all the groups to be compared.
During the experiment, 28 persons (7.0 %) refused to par cipate in it.Among them, from group А -13 people (3.2 %) belonged to the Group A, 7 people (1.7 %) belonged to the Group B and 8 people (2.0 %) belonged to the Group A. The reasons of refusal were-acute infl ammatory diseases (10 cases (2.5 %),nega ve psycho-emo onal response to Alarm-therapy (7 cases (1.7 %), and other reasons that were not related to the treatment 11 cases (2.7 %).

Discussion
In our opinion, the obtained results allow to assume that sensibility of non-adults to the therapy with the use of alarm systems essen ally changes with age.
Ini al data allow concluding that children of junior and average age subgroups show op mal response to conducted therapy.However, if the result of 10-12-year-old children proved to be stable, the result of 7-9-year-old children was signifi cantly worse within 2 months a er the end of treatment.
In our opinion, one of the explana ons of these results could be features of growth and development of central regions autonomic nerve system in this age among children who suff er from PMNE.The responses of such autonomic system to irritators probably turn weaker among older children who suff er from enuresis, comparing with younger ones.Central and peripheral structures of the autonomic system loose lability (or course, rela vely), while development and fi xa on of condi oned refl ex links are carried out less eff ec vely 23,24,25,26 .It may be one of the reasons for weaker response of the pa ents of senior age group to suggested therapy algorithm.
In this regard, the study that has been recently carried out by Lei D et al (2012) to study the changes in spontaneous ac vity and microstructure of various brain regions among children and teenagers who suff er from PMNE 27,28 , using magne c resonance imaging (MRI), seem to be interes ng.Substan al diff erences in basic rhythms of le lower frontal gyrus, medial frontal gyrus and some other brain regions related to data processing were detected among children who suff er from PMNE.Microstructural failures were detected in thalamus, medial frontal gyrus and other regions related to the regula on of urine output.The authors of this study argue that detected anomalies may have an impact on the transmission of neural signals that regulate bladder func on and on the processes related to awakening.The authors also assume that delay in normal development and diff eren a on of studied fi elds may cause the emergence of PMNE.Esposito M et al (2013) 29 also point out to the necessity of taking into account the delay in development of central regions of autonomic nerve system and immaturity of nerve and refl ex mechanisms when establishing diagnosis and choosing therapy for children who suff er from PMNE.
It is probably microstructural failures and, subsequently, func onal immaturity of autonomic nerve system that are of the reasons for diff erent response of children of various age to the standard algorithm of the Alarm-therapy.In this view, rela ve instability and easy loss of newly acquired skill exactly among children of younger age seem to be understandable too.
In their review of enuresis therapy methods, based on the results of eight recent studies, Perrin N  et al (2013) report that prolonged use of the Alarm interven on achieves be er results than taking desmopressin 30 .Ahmed AF et al. (2013) also point out to be er result achieved by using signal systems and its higher survival, compared to desmopressin, which can be interpreted as important indirect evidence of delay of autonomic nerve system development among children of younger age 31 .Thus, rela vely high func onal elas city, easiness of development and fi xa on of conven onal-refl ex connec ons are typical for 7-12-year-old children.However, the the other side of this process is rela ve instability and easy loss of newly acquired skills [32][33] .In our experiment, quick forma on of condi oned refl ex of awakening in case of desire to urinate resulted with their equally quick loss among younger children lost it quickly a er the end of alarm systems use, while older pa ents had more stable eff ect.

Conclusion
Children of the age group 7-9 and 10-12-year-old were most sensi ve to the alarm therapy of PMNE.However, in case of younger children, the eff ect of increase in the number of dry nights, acquiring skill of awakening in case of desire to urinate and reduc on in the number of episodes of incon nence in sleep signifi cantly declined within two months.The signs of alarm interven on of enuresis among 13-15-year-old children were less effi cient, but the result was more stable.The results thus obtained, by all means, cannot be considered as suffi cient and require further studies however alarm interven on had the best direct and long-term eff ect on 10-12-year old children.

Figures 2
Figures 2 and 3 represent monthly dynamics of average number of dry nights and enuresis episodes during the experiment.

Figures 2 and 3 ,
Figures 2 and 3, show monthly changes in average numbers of dry nights and enuresis episodes during the experiment.

Fig 2 :Fig 1 :Fig 3 :Fig 4 :
Fig 2:The change in frequency of episodes of "dry" nights (per week) with alarm therapy in diff erent age groups (n = 399)