- Email: [email protected]
MONOSYMPTOMATIC NOCTURNAL ENURESIS IS ASSOCIATED WITH ABNORMAL NOCTURNAL BLADDER EMPTYING
0022-5347/04/1716-2562/0 THE JOURNAL OF UROLOGY® Copyright © 2004 by AMERICAN UROLOGICAL ASSOCIATION
Vol. 171, 2562–2566, June 2004 Printed in U.S.A.
DOI: 10.1097/01.ju.0000110882.31824.89
Noctural Enuresis: Pathophysiology MONOSYMPTOMATIC NOCTURNAL ENURESIS IS ASSOCIATED WITH ABNORMAL NOCTURNAL BLADDER EMPTYING S. HAGSTROEM, K. KAMPERIS, S. RITTIG,* N. J. M. RIJKHOFF
AND
J. C. DJURHUUS
From the Institute of Experimental Clinical Research, University of Aarhus (SH, KK, JCD) and Department of Pediatrics, Skejby University Hospital (SR), Aarhus, and Center for Sensory-Motor Interaction, Aalborg University (NJMR), Aalborg, Denmark
ABSTRACT
Purpose: We investigate the nature of enuresis episodes in monosymptomatic nocturnal enuresis using a fluid provocation model. Materials and Methods: The study included 18 children 7 to 13 years old with monosymptomatic nocturnal enuresis. Based on basal home recordings patients were subgrouped into those with a normal nocturnal urine output and those with nocturnal polyuria (mean nocturnal urine production on wet nights exceeding 130% of functional bladder capacity, normal functional bladder capacity for age provided). Children were admitted to the hospital for 4 consecutive nights. After an adaptation night all children received orally 25 ml/kg water, 30 minutes before bedtime on the remaining 3 nights. A cordless alarm device enabled registration of enuretic episodes from another room and diapers allowed the measurement of enuresis volumes. Post-void residual volumes were measured by ultrasound. Pelvic floor electromyography was continuously recorded throughout the night, and its association to bladder emptying was investigated. Results: A total of 95 enuresis and 14 nocturia episodes were recorded. Significantly more enuresis episodes were registered on nights with oral fluid load, whereas no increase in number of nocturia episodes was seen. Of the enuresis episodes 46 were associated with incomplete bladder emptying (post-void residual volume greater than 10% of total bladder volume at time of enuresis). No difference between patient groups regarding post-void residual volume was seen. Abnormal bursts of electromyography activity were associated with incomplete micturitions. Conclusions: Enuresis nocturna episodes in polyuric and nonpolyuric patients are frequently incomplete micturitions. The present findings question the definition of nocturnal enuresis episode as normal complete voiding. KEY WORDS: enuresis, polyuria, pelvic floor electromyography
Monosymptomatic nocturnal enuresis (MNE) is a common disorder with an estimated prevalence of 5% to 10% at age 7 years and a spontaneous cure rate of 15% per year.1, 2 Despite the high cure rate, the disorder persists into adulthood to a considerable degree and nocturnal enuresis is seen in approximately 0.5% to 1% of adults. The exact etiology has not been fully defined yet, but several pathophysiological mechanisms seem to be implicated. It is generally accepted that enuresis occurs when the child lacks the ability to suppress the micturition reflex during sleep or urinary output exceeds the capacity of the bladder and the child fails to awaken. The definition of nocturnal enuresis has been a matter of great debate through the years. The age at which it is acceptable to regard bedwetting as a disorder has been argued. Some scientists consider voiding taking place in an inappropriate or socially unacceptable time or place to be an illness regardless of the age of the child,3 whereas others find it inappropriate to consider incontinence pathological before the age of 5 years.2, 4 Based on the current experimental data, however, MNE is still defined as normal voiding during sleep at an age when continence should have been attained and in
the absence of daytime symptoms.3, 5 The nocturnal enuresis episode has been assumed to be complete emptying of the bladder, based mainly on few and often invasive studies.3, 4 Sleep cystometries have characterized the enuretic episode as a complete, urodynamically normal, voiding.6 However, these findings were contradicted when fluid provocation was used as a noninvasive model for the study of nocturnal micturition. A significant number of enuresis-like episodes with incomplete emptying have been seen in continent children as the result of excess fluid intake at bedtime.7, 8 These data emphasize the need for reevaluation of the definition of enuresis. We investigate the nature of the enuresis episode in children with MNE using a noninvasive fluid provocation model. Apart from evaluating the validity of the model, we determined whether induced nocturnal polyuria results in enuresis or nocturia and whether the enuretic episode was associated with complete emptying. Pelvic floor electromyography (EMG) was used to assess the enuresis episodes and test the hypothesis that incomplete bladder emptying is related to inhibitory activity of the pelvic floor.
Study received local Ethical Committee approval. MATERIALS AND METHODS * Correspondence: Department of Pediatrics A, Skejby University Children were recruited for study from the Center of Child Hospital, DK-8200 Aarhus N, Denmark (telephone: ⫹45 8949 6773; Incontinence, Skejby University Hospital, Aarhus, Denmark. FAX: ⫹45 8949 6011; e-mail: [email protected]). 2562
MONOSYMPTOMATIC NOCTURNAL ENURESIS AND ABNORMAL NOCTURNAL BLADDER EMPTYING
A total of 18 children with MNE, age 7 to 13 years, had enuresis frequency of at least 3 nights a week, lack of daytime incontinence or frequency, unremarkable clinical examination and normal uroflowmetry, no post-void residual urine during the day defined as less than 20 ml or 10% of voided volume, and normal plasma electrolytes, creatinine, blood urea nitrogen, albumin, hemoglobin and urinalysis. The local Ethical Committee of Aarhus County approved the study. During the runin period participants were asked to perform home recordings for 14 consecutive days consisting of registration of enuresis volumes using diaper weighing,9 nocturia and morning voidings, as well as 4, 24-hour frequencyvolume charts during weekends. Functional bladder capacity (FBC) was defined as the largest voiding reported including morning voids. According to the data obtained from the home recordings, nocturnal polyuria was defined as mean nocturnal urine production on wet nights exceeding 130% of FBC with otherwise normal FBC (greater than 70% of expected for age)10 and nonpolyuria was considered when nocturnal urine output was below this limit. The subjects were admitted to the hospital for 4 consecutive nights. During the day they were at home with free fluid intake. The first night was used for baseline measurements. On the remaining 3 nights all children received orally 25 ml/kg water load of body weight with a maximum of 1,000 ml within half an hour before bedtime. Samples of evening urine were collected for urinalysis before administration of the water load. All voluntary micturitions including nocturia episodes were recorded with uroflowmetry, and the volume and time of micturition were noted. During all 4 nights the children used a diaper in which an enuresis sensor was fastened. During an enuresis episode the signal from the sensor was cordlessly transmitted to a computer for registration and to an alarm device in another room, ensuring that the children could not hear the alarm. When enuresis occurred, the residual urine was measured within 60 seconds of initiation of the voiding by the investigators using ultrasound, and the diaper was replaced and weighed. Care was taken to disturb the child as little as possible. The time to bed, the time at which enuresis or nocturia episodes occurred as well as arousal time were registered. Post-void residual volumes (PVR) were measured using Bladderscan BVI 2500⫹ (Diagnostic Ultrasound, Bothell, Washington).11 PVR of more than 10% of the bladder volume at the time of enuresis (enuresis voided volume ⫹ PVR) was considered clinically significant. Electromyography. Pelvic floor EMG signals were amplified using a Dantec Counterpoint (Dantec Dynamics, Skov-
2563
lunde, Denmark), sampled and digitized using a NI 6023E board and stored on a personal computer. A custom made LabVIEW program was used for data acquisition and analysis (National Instruments Corp., Austin, Texas). A sampling frequency of 150 Hz was used with low pass cutoff at 20 Hz and high pass cutoff at 5 kHz. Three EMG surface electrodes were used, (Blue Sensor disposal electrocardiogram electrodes NF-50-K, Medicotest, Oelstykka, Denmark), including 2 positioned at 2 and 10 o’clock perianally and 1 reference electrode placed above the major trochanter. The analysis of increase in EMG amplitude of the recordings was performed without prior knowledge of the degree of bladder emptying. Silent EMG (no EMG activity) was defined as the amplitude recorded with relaxed pelvic floor and when the child was awake. Statistical analysis. Results are reported as means ⫾ standard deviation unless otherwise stated. Student’s t test was used for comparisons between the 2 groups of participants, while ANOVA for repeated measurements was used for comparisons between baseline and fluid provocation nights, with p ⬍0.05 considered statistically significant. RESULTS
Table 1 shows the demographic data of the 18 study participants. Based on home recordings 7 children had nocturnal polyuria and 11 did not. A total of 95 nocturnal enuresis and 14 nocturia episodes were recorded. All 18 children had at least 1 nocturnal enuresis episode during the trial. Significantly more enuresis episodes were registered on nights with oral fluid load in comparison to the baseline night (ANOVA ptime ⬍0.05), while there was no increase in the number of nocturia episodes on the night of fluid provocation compared to the baseline night (ANOVA ptime ⫽ 0.31, fig. 1). No differences in the occurrence of enuresis or nocturia between the 2 groups were seen as assessed by ANOVA. Only 2 nonpolyuric children had only 1 episode of enuresis during the trial. There was no significant difference in the overall number of enuresis episodes between the 2 patient groups (p ⫽ 0.74). Seven patients had nocturia during the study (more than once in 3). One child had 5 episodes of nocturia but none had more than 2 episodes a night. All but 1 patient who had nocturia episodes also experienced enuresis during the same night. All children who had nocturia during 1 or more of the 4 study nights had also reported episodes of nocturia during the home recording period. Figure 2 shows the time of occurrence of the first enuresis episodes. Generally, on the nights of fluid provocation the first enuresis episodes occurred ear-
TABLE 1. Demographic data, FBC and FBC-to-FBC expected for age ratio Age — Sex — Ht —Body (cm) Wt (kg)
FBC (ml)
7— 7— 8— 9— 9— 10 — 10 —
M F F F F F M
— — — — — — —
134 131 138 138 152 157 146
— — — — — — —
29 30 36 30 36 48 33
200 160 320 260 262 290 250
7— 7— 8— 9— 9— 10 — 10 — 10 — 11 — 12 — 13 —
M F F F M M F M M M M
— — — — — — — — — — —
131 124 133 140 158 150 147 143 150 162 157
— — — — — — — — — — —
28 24 29 27 52 47 40 38 44 56 42
230 150 170 123 400 400 200 200 210 225 250
FBC:FBC for Age Ratio (%) Nocturnal polyuria 0.83 0.76 1.19 0.87 0.87 0.88 0.76 No nocturnal polyuria 0.96 0.63 0.63 0.47 1.33 1.21 0.61 0.61 0.58 0.58 0.60
Urine Output Wet Nights (ml)
Mean ⫾ SD PVR (ml)
375.4 245.9 489 361 411 382.5 384
22.9 ⫾ 30.2 100.6 ⫾ 95.3 50.6 ⫾ 58.9 41.3 ⫾ 71.6 118.0 ⫾ 236.0 59.5 ⫾ 84.2 51.6 ⫾ 53.3
246.7 195 249 245.2 262.8 388.9 222.1 291 — 395.3 234.5
110.9 ⫾ 93.7 16.0 ⫾ 25.5 1.8 ⫾ 3.5 52.3 ⫾ 64.0 138.0 ⫾ 100.5 97.3 ⫾ 59.23 — — 63.5 ⫾ 73.3 99.3 ⫾ 86.0 7.8 ⫾ 9.0
2564
MONOSYMPTOMATIC NOCTURNAL ENURESIS AND ABNORMAL NOCTURNAL BLADDER EMPTYING
FIG. 1. Distribution of nocturnal enuresis and nocturia episodes during 4 study nights. Significantly more enuresis episodes were registered on nights with oral water load compared to baseline night (ptime ⬍0.05), while there was no increase in number of nocturia episodes on nights with fluid provocation compared to baseline night (ptime ⫽ 0.31).
FIG. 3. Distribution of enuresis episodes in relation to significant PVR volume (black bars) and total number of enuresis episodes (gray bars).
ure 4 shows examples of the different pelvic floor EMG activity recorded during episodes of nocturnal enuresis. When pelvic floor activity was recorded during voiding all micturitions were associated with incomplete bladder emptying, whereas 29 of 31 enuresis episodes with no EMG activity during micturition (silent EMG for at least 25 seconds after initiation of voiding) were complete voidings (table 2). In 4 cases both patterns of EMG activity were present during the same night. For the remaining 26 enuresis episodes no EMG activity was present before, during or after the episode, and these were equally associated with complete and incomplete bladder emptying. DISCUSSION
FIG. 2. Time lapse in minutes from bedtime to occurrence of first enuresis episodes in patients with (circles) and without (squares) nocturnal polyuria.
lier compared to the baseline night (114 ⫾ 86 vs to 253 ⫾ 80 minutes, p ⬍0.01). Furthermore, on the baseline nights enuresis episodes occurred earlier for children with polyuria than for those without polyuria (194 ⫾ 68 vs to 324 ⫾ 56, p ⬍0.05). The nocturnal enuresis episodes were associated with incomplete bladder emptying, with a significant post-void residual volume in 46 of 95 (48.4%) enuresis episodes. In patients with nocturnal polyuria 20 of 39 (51.3%) enuresis episodes were associated with incomplete bladder emptying and residual urine was seen in 26 of 56 (46.4%) patients without polyuria. Nocturnal enuresis episodes with PVR were seen during baseline nights to the same degree as on the nights of fluid provocation. Figure 3 shows an equal distribution of incomplete micturitions on the 4 study nights. Overall, the mean PVR was 63.5 ⫾ 95.5 ml for patients with and 64.3 ⫾ 78.4 ml for patients without polyuria (table 1). EMG recordings of 70 nocturnal enuresis episodes were obtained. In 44 cases a degree of pelvic floor activity was recorded in conjunction with voiding (before, during or after) and in 13 of them activity during micturition (less than 7 seconds after initiation of micturition) became evident. Fig-
To investigate the nature of the enuretic episode in MNE we used a noninvasive model of fluid provocation. The validity of the model can be substantiated by the fact that the excess fluid intake at bedtime led to episodes of enuresis rather than nocturia. Since the same model was previously used in healthy children of approximately the same age it is justifiable to compare the 2 studies. The response to fluid intake in the present study was different from that observed in healthy children receiving comparable amounts of water before bedtime, where by far the most common response was nocturia.7 Therefore, there may be differences between enuretics and normals regarding their awareness of and response to bladder filling during sleep. Polysomnographic studies of enuresis children led to analogous speculations demonstrating that these children share higher arousal thresholds12, 13 and the present study supports these findings. Electroencephalogram recordings were not performed in our study since evaluation of sleep patterns was beyond its scope, although the present model may be used for studies of the architecture of sleep in enuresis children. WHO defines the enuresis episode as normal and complete voiding.5 In our study significant amounts of residual urine were seen in nearly half of the nocturnal enuresis episodes and interestingly all but 2 of the participants experienced episodes with PVR. Nocturnal enuresis episodes with PVR were seen during baseline nights to the same degree as during the nights with fluid provocation, indicating that the degree of bladder emptying is apparently not influenced by polyuria per se. We found no differences in the number of enuresis episodes with incomplete emptying between those with and without polyuria. These striking observations support that incomplete bladder emptying is a common phenomenon in monosymptomatic
MONOSYMPTOMATIC NOCTURNAL ENURESIS AND ABNORMAL NOCTURNAL BLADDER EMPTYING
2565
FIG. 4. Examples of different pelvic floor EMG activity recorded during episodes of nocturnal enuresis. Arrows mark time of activation of enuresis alarm. A, presence of pelvic floor activity during micturition. B, no activity during voiding. C, complete EMG silence before, during and after nocturnal enuresis episode.
TABLE 2. Association between pelvic floor EMG activity and degree of bladder emptying during enuresis episodes Pelvic Floor EMG Activity during voiding phase No activity during voiding phase No EMG activity before, during or after enuresis episode
No. Significant PVR
No. Nonsignificant PVR
13 2 12
0 29 14
nocturnal enuresis occurring just as frequently as complete bladder emptying and refute the previous assumptions of enuresis being a complete voiding.3 An explanation for this finding could be that until now the enuresis episode had been evaluated using cystometric methods, which may provide accurate information on bladder dynamics during the night, but may not be the optimal method to study bladder emptying. The recordings of pelvic floor activity enabled us to elucidate the background behind incomplete bladder emptying. In all 13 cases with bursts of pelvic floor activity during voiding there was a significant PVR, corroborating previous findings of provoked enuresis in healthy children.7 It is plausible that during sleep children are able to interrupt micturition by activating the pelvic floor, and this involuntary withholding ability is likely to originate from the pontine micturition center. The absence of pelvic floor activity after initiation of micturition in 29 of 31 complete voidings indicates that the child was not able to suppress the micturition reflex. The EMG pattern seen in these cases is to some extent similar to that described for normal voiding at the awake state when no pelvic floor activity is seen after initiation of micturition.14 The fact that some children presented with both patterns of EMG activity during the same night could lead to the hypothesis that this fact is due to differences in the sleep stages in which enuresis occurs.12 Our findings are also in concordance with previous studies indicating a
general dysfunction of the brainstem maturation in patients with enuresis.15 In 26 cases we were unable to record any activity in the pelvic floor before and after initiation of the enuresis. Since an equal distribution of enuresis episodes with and without PVR was found in these cases, it can be speculated that this lack of pelvic floor activity is actually the result of insufficient EMG sampling. Similar observations were previously made of sleep cystometries in enuretic children with silent pelvic floor EMG.3 Since pelvic floor EMG recording during sleep is difficult, interpretations of silent EMG recordings should be made with particular caution. CONCLUSIONS
Fluid provocation is a valid noninvasive model for investigating the nature of nocturnal enuresis episode in children with monosymptomatic nocturnal enuresis. The induced polyuria leads to enuresis rather than nocturia, indicating failure of these children to awaken to a full bladder regardless of the type of enuresis. Incomplete bladder emptying is a frequent phenomenon in monosymptomatic nocturnal enuresis and is encountered to the same extent in children with and without polyuria. When pelvic floor activity is present during micturition it is associated with incomplete bladder emptying. Silent EMG patterns during micturitions similar to those seen during normal voidings in the awake state are generally associated with complete bladder emptying. The findings are in contrast to the current definition of monosymptomatic nocturnal enuresis as normal voiding with complete emptying. Therefore, reappraisal of the definition is suggested. REFERENCES
1. Fergusson, D. M., Horwood, L. J. and Shannon, F. T.: Factors related to the age of attainment of nocturnal bladder control: an 8-year longitudinal study. Pediatrics, 78: 884, 1986
2566
MONOSYMPTOMATIC NOCTURNAL ENURESIS AND ABNORMAL NOCTURNAL BLADDER EMPTYING
2. Forsythe, W. I. and Redmond, A.: Enuresis and spontaneous cure rate. Study of 1129 enuretis. Arch Dis Child, 49: 259, 1974 3. Norgaard, J. P.: Pathophysiology of nocturnal enuresis. Scand J Urol Nephrol, suppl., 140: 1, 1991 4. Hjalmas, K.: Urinary incontinence in children: suggestions for definitions and terminology. Scand J Urol Nephrol, suppl., 141: 1, 1992 5. Abrams, P., Khoury, S. and Wein, A.: 1st International Consultation on Incontinence, 1998 6. Norgaard, J. P., Hansen, J. H., Wildschiotz, G., Sorensen, S., Rittig, S. and Djurhuus, J. C.: Sleep cystometries in children with nocturnal enuresis. J Urol, 141: 1156, 1989 7. Kirk, J., Rasmussen, P. V., Rittig, S. and Djurhuus, J. C.: Provoked enuresis-like episodes in healthy children 7 to 12 years old. J Urol, 156: 210, 1996 8. Rasmussen, P. V., Kirk, J., Rittig, S. and Djurhuus, J. C.: The enuretic episode—a complete micturition from a bladder with normal capacity? A critical reappraisal of the definition. Scand J Urol Nephrol, suppl., 183: 23, 1997 9. Hansen, M. N., Rittig, S., Siggaard, C., Kamperis, K., Hvistendahl, G., Schaumburg, H. L. et al: Intra-individual variability in nighttime urine production and functional bladder capacity estimated by home recordings in patients with nocturnal enuresis. J Urol, 166: 2452, 2001 10. Koff, S. A.: Estimating bladder capacity in children. Urology, 21: 248, 1983 11. Coombes, G. M. and Millard, R. J.: The accuracy of portable ultrasound scanning in the measurement of residual urine volume. J Urol, 152: 2083, 1994 12. Wolfish, N. M., Pivik, R. T. and Busby, K. A.: Elevated sleep arousal thresholds in enuretic boys: clinical implications. Acta
Paediatr, 86: 381, 1997 13. Hunsballe, J.: Sleep studies based on electroencephalogram energy analysis. Scand J Urol Nephrol, suppl., 202: 28, 1999 14. Binnie, C. D., Fowler, C. J., Cooper, R., Mauguiere, F. and Prior, P. F.: Clinical Neurophysiology. Oxford: Butterworth-Heinemann, p. 4, 1995 15. von Gontard, A., Schmelzer, D., Seifen, S. and Pukrop, R.: Central nervous system involvement in nocturnal enuresis: evidence of general neuromotor delay and specific brainstem dysfunction. J Urol, 166: 2448, 2001 EDITORIAL COMMENT This is an excellent study of nocturnal enuresis using noninvasive technology so that recordings are as physiological as possible. These authors found that nocturnal enuresis episodes are associated with incomplete emptying. The WHO definition should be modified if other investigators are able to reproduce the study and the findings hold true for a larger number of patients. The clinical impact of this finding depends on the incidence of abnormal emptying in the population with nocturnal enuresis, which was not addressed in this study. Only the percentage of incomplete emptying among total episodes of enuresis for the group was noted. The mean post-void residual of the group was calculated. To assess severity and/or significance of abnormal emptying one would also like to know the post-void residual/functional bladder capacity. In summary, these authors found important characteristics of nocturnal enuresis by designing a study that should be reproducible and enable further investigation of this common pediatric problem. Jean G. Hollowell Fredrickson Outpatient Center Mechanicsburg, Pennsylvania
Vol. 171, 2562–2566, June 2004 Printed in U.S.A.
DOI: 10.1097/01.ju.0000110882.31824.89
Noctural Enuresis: Pathophysiology MONOSYMPTOMATIC NOCTURNAL ENURESIS IS ASSOCIATED WITH ABNORMAL NOCTURNAL BLADDER EMPTYING S. HAGSTROEM, K. KAMPERIS, S. RITTIG,* N. J. M. RIJKHOFF
AND
J. C. DJURHUUS
From the Institute of Experimental Clinical Research, University of Aarhus (SH, KK, JCD) and Department of Pediatrics, Skejby University Hospital (SR), Aarhus, and Center for Sensory-Motor Interaction, Aalborg University (NJMR), Aalborg, Denmark
ABSTRACT
Purpose: We investigate the nature of enuresis episodes in monosymptomatic nocturnal enuresis using a fluid provocation model. Materials and Methods: The study included 18 children 7 to 13 years old with monosymptomatic nocturnal enuresis. Based on basal home recordings patients were subgrouped into those with a normal nocturnal urine output and those with nocturnal polyuria (mean nocturnal urine production on wet nights exceeding 130% of functional bladder capacity, normal functional bladder capacity for age provided). Children were admitted to the hospital for 4 consecutive nights. After an adaptation night all children received orally 25 ml/kg water, 30 minutes before bedtime on the remaining 3 nights. A cordless alarm device enabled registration of enuretic episodes from another room and diapers allowed the measurement of enuresis volumes. Post-void residual volumes were measured by ultrasound. Pelvic floor electromyography was continuously recorded throughout the night, and its association to bladder emptying was investigated. Results: A total of 95 enuresis and 14 nocturia episodes were recorded. Significantly more enuresis episodes were registered on nights with oral fluid load, whereas no increase in number of nocturia episodes was seen. Of the enuresis episodes 46 were associated with incomplete bladder emptying (post-void residual volume greater than 10% of total bladder volume at time of enuresis). No difference between patient groups regarding post-void residual volume was seen. Abnormal bursts of electromyography activity were associated with incomplete micturitions. Conclusions: Enuresis nocturna episodes in polyuric and nonpolyuric patients are frequently incomplete micturitions. The present findings question the definition of nocturnal enuresis episode as normal complete voiding. KEY WORDS: enuresis, polyuria, pelvic floor electromyography
Monosymptomatic nocturnal enuresis (MNE) is a common disorder with an estimated prevalence of 5% to 10% at age 7 years and a spontaneous cure rate of 15% per year.1, 2 Despite the high cure rate, the disorder persists into adulthood to a considerable degree and nocturnal enuresis is seen in approximately 0.5% to 1% of adults. The exact etiology has not been fully defined yet, but several pathophysiological mechanisms seem to be implicated. It is generally accepted that enuresis occurs when the child lacks the ability to suppress the micturition reflex during sleep or urinary output exceeds the capacity of the bladder and the child fails to awaken. The definition of nocturnal enuresis has been a matter of great debate through the years. The age at which it is acceptable to regard bedwetting as a disorder has been argued. Some scientists consider voiding taking place in an inappropriate or socially unacceptable time or place to be an illness regardless of the age of the child,3 whereas others find it inappropriate to consider incontinence pathological before the age of 5 years.2, 4 Based on the current experimental data, however, MNE is still defined as normal voiding during sleep at an age when continence should have been attained and in
the absence of daytime symptoms.3, 5 The nocturnal enuresis episode has been assumed to be complete emptying of the bladder, based mainly on few and often invasive studies.3, 4 Sleep cystometries have characterized the enuretic episode as a complete, urodynamically normal, voiding.6 However, these findings were contradicted when fluid provocation was used as a noninvasive model for the study of nocturnal micturition. A significant number of enuresis-like episodes with incomplete emptying have been seen in continent children as the result of excess fluid intake at bedtime.7, 8 These data emphasize the need for reevaluation of the definition of enuresis. We investigate the nature of the enuresis episode in children with MNE using a noninvasive fluid provocation model. Apart from evaluating the validity of the model, we determined whether induced nocturnal polyuria results in enuresis or nocturia and whether the enuretic episode was associated with complete emptying. Pelvic floor electromyography (EMG) was used to assess the enuresis episodes and test the hypothesis that incomplete bladder emptying is related to inhibitory activity of the pelvic floor.
Study received local Ethical Committee approval. MATERIALS AND METHODS * Correspondence: Department of Pediatrics A, Skejby University Children were recruited for study from the Center of Child Hospital, DK-8200 Aarhus N, Denmark (telephone: ⫹45 8949 6773; Incontinence, Skejby University Hospital, Aarhus, Denmark. FAX: ⫹45 8949 6011; e-mail: [email protected]). 2562
MONOSYMPTOMATIC NOCTURNAL ENURESIS AND ABNORMAL NOCTURNAL BLADDER EMPTYING
A total of 18 children with MNE, age 7 to 13 years, had enuresis frequency of at least 3 nights a week, lack of daytime incontinence or frequency, unremarkable clinical examination and normal uroflowmetry, no post-void residual urine during the day defined as less than 20 ml or 10% of voided volume, and normal plasma electrolytes, creatinine, blood urea nitrogen, albumin, hemoglobin and urinalysis. The local Ethical Committee of Aarhus County approved the study. During the runin period participants were asked to perform home recordings for 14 consecutive days consisting of registration of enuresis volumes using diaper weighing,9 nocturia and morning voidings, as well as 4, 24-hour frequencyvolume charts during weekends. Functional bladder capacity (FBC) was defined as the largest voiding reported including morning voids. According to the data obtained from the home recordings, nocturnal polyuria was defined as mean nocturnal urine production on wet nights exceeding 130% of FBC with otherwise normal FBC (greater than 70% of expected for age)10 and nonpolyuria was considered when nocturnal urine output was below this limit. The subjects were admitted to the hospital for 4 consecutive nights. During the day they were at home with free fluid intake. The first night was used for baseline measurements. On the remaining 3 nights all children received orally 25 ml/kg water load of body weight with a maximum of 1,000 ml within half an hour before bedtime. Samples of evening urine were collected for urinalysis before administration of the water load. All voluntary micturitions including nocturia episodes were recorded with uroflowmetry, and the volume and time of micturition were noted. During all 4 nights the children used a diaper in which an enuresis sensor was fastened. During an enuresis episode the signal from the sensor was cordlessly transmitted to a computer for registration and to an alarm device in another room, ensuring that the children could not hear the alarm. When enuresis occurred, the residual urine was measured within 60 seconds of initiation of the voiding by the investigators using ultrasound, and the diaper was replaced and weighed. Care was taken to disturb the child as little as possible. The time to bed, the time at which enuresis or nocturia episodes occurred as well as arousal time were registered. Post-void residual volumes (PVR) were measured using Bladderscan BVI 2500⫹ (Diagnostic Ultrasound, Bothell, Washington).11 PVR of more than 10% of the bladder volume at the time of enuresis (enuresis voided volume ⫹ PVR) was considered clinically significant. Electromyography. Pelvic floor EMG signals were amplified using a Dantec Counterpoint (Dantec Dynamics, Skov-
2563
lunde, Denmark), sampled and digitized using a NI 6023E board and stored on a personal computer. A custom made LabVIEW program was used for data acquisition and analysis (National Instruments Corp., Austin, Texas). A sampling frequency of 150 Hz was used with low pass cutoff at 20 Hz and high pass cutoff at 5 kHz. Three EMG surface electrodes were used, (Blue Sensor disposal electrocardiogram electrodes NF-50-K, Medicotest, Oelstykka, Denmark), including 2 positioned at 2 and 10 o’clock perianally and 1 reference electrode placed above the major trochanter. The analysis of increase in EMG amplitude of the recordings was performed without prior knowledge of the degree of bladder emptying. Silent EMG (no EMG activity) was defined as the amplitude recorded with relaxed pelvic floor and when the child was awake. Statistical analysis. Results are reported as means ⫾ standard deviation unless otherwise stated. Student’s t test was used for comparisons between the 2 groups of participants, while ANOVA for repeated measurements was used for comparisons between baseline and fluid provocation nights, with p ⬍0.05 considered statistically significant. RESULTS
Table 1 shows the demographic data of the 18 study participants. Based on home recordings 7 children had nocturnal polyuria and 11 did not. A total of 95 nocturnal enuresis and 14 nocturia episodes were recorded. All 18 children had at least 1 nocturnal enuresis episode during the trial. Significantly more enuresis episodes were registered on nights with oral fluid load in comparison to the baseline night (ANOVA ptime ⬍0.05), while there was no increase in the number of nocturia episodes on the night of fluid provocation compared to the baseline night (ANOVA ptime ⫽ 0.31, fig. 1). No differences in the occurrence of enuresis or nocturia between the 2 groups were seen as assessed by ANOVA. Only 2 nonpolyuric children had only 1 episode of enuresis during the trial. There was no significant difference in the overall number of enuresis episodes between the 2 patient groups (p ⫽ 0.74). Seven patients had nocturia during the study (more than once in 3). One child had 5 episodes of nocturia but none had more than 2 episodes a night. All but 1 patient who had nocturia episodes also experienced enuresis during the same night. All children who had nocturia during 1 or more of the 4 study nights had also reported episodes of nocturia during the home recording period. Figure 2 shows the time of occurrence of the first enuresis episodes. Generally, on the nights of fluid provocation the first enuresis episodes occurred ear-
TABLE 1. Demographic data, FBC and FBC-to-FBC expected for age ratio Age — Sex — Ht —Body (cm) Wt (kg)
FBC (ml)
7— 7— 8— 9— 9— 10 — 10 —
M F F F F F M
— — — — — — —
134 131 138 138 152 157 146
— — — — — — —
29 30 36 30 36 48 33
200 160 320 260 262 290 250
7— 7— 8— 9— 9— 10 — 10 — 10 — 11 — 12 — 13 —
M F F F M M F M M M M
— — — — — — — — — — —
131 124 133 140 158 150 147 143 150 162 157
— — — — — — — — — — —
28 24 29 27 52 47 40 38 44 56 42
230 150 170 123 400 400 200 200 210 225 250
FBC:FBC for Age Ratio (%) Nocturnal polyuria 0.83 0.76 1.19 0.87 0.87 0.88 0.76 No nocturnal polyuria 0.96 0.63 0.63 0.47 1.33 1.21 0.61 0.61 0.58 0.58 0.60
Urine Output Wet Nights (ml)
Mean ⫾ SD PVR (ml)
375.4 245.9 489 361 411 382.5 384
22.9 ⫾ 30.2 100.6 ⫾ 95.3 50.6 ⫾ 58.9 41.3 ⫾ 71.6 118.0 ⫾ 236.0 59.5 ⫾ 84.2 51.6 ⫾ 53.3
246.7 195 249 245.2 262.8 388.9 222.1 291 — 395.3 234.5
110.9 ⫾ 93.7 16.0 ⫾ 25.5 1.8 ⫾ 3.5 52.3 ⫾ 64.0 138.0 ⫾ 100.5 97.3 ⫾ 59.23 — — 63.5 ⫾ 73.3 99.3 ⫾ 86.0 7.8 ⫾ 9.0
2564
MONOSYMPTOMATIC NOCTURNAL ENURESIS AND ABNORMAL NOCTURNAL BLADDER EMPTYING
FIG. 1. Distribution of nocturnal enuresis and nocturia episodes during 4 study nights. Significantly more enuresis episodes were registered on nights with oral water load compared to baseline night (ptime ⬍0.05), while there was no increase in number of nocturia episodes on nights with fluid provocation compared to baseline night (ptime ⫽ 0.31).
FIG. 3. Distribution of enuresis episodes in relation to significant PVR volume (black bars) and total number of enuresis episodes (gray bars).
ure 4 shows examples of the different pelvic floor EMG activity recorded during episodes of nocturnal enuresis. When pelvic floor activity was recorded during voiding all micturitions were associated with incomplete bladder emptying, whereas 29 of 31 enuresis episodes with no EMG activity during micturition (silent EMG for at least 25 seconds after initiation of voiding) were complete voidings (table 2). In 4 cases both patterns of EMG activity were present during the same night. For the remaining 26 enuresis episodes no EMG activity was present before, during or after the episode, and these were equally associated with complete and incomplete bladder emptying. DISCUSSION
FIG. 2. Time lapse in minutes from bedtime to occurrence of first enuresis episodes in patients with (circles) and without (squares) nocturnal polyuria.
lier compared to the baseline night (114 ⫾ 86 vs to 253 ⫾ 80 minutes, p ⬍0.01). Furthermore, on the baseline nights enuresis episodes occurred earlier for children with polyuria than for those without polyuria (194 ⫾ 68 vs to 324 ⫾ 56, p ⬍0.05). The nocturnal enuresis episodes were associated with incomplete bladder emptying, with a significant post-void residual volume in 46 of 95 (48.4%) enuresis episodes. In patients with nocturnal polyuria 20 of 39 (51.3%) enuresis episodes were associated with incomplete bladder emptying and residual urine was seen in 26 of 56 (46.4%) patients without polyuria. Nocturnal enuresis episodes with PVR were seen during baseline nights to the same degree as on the nights of fluid provocation. Figure 3 shows an equal distribution of incomplete micturitions on the 4 study nights. Overall, the mean PVR was 63.5 ⫾ 95.5 ml for patients with and 64.3 ⫾ 78.4 ml for patients without polyuria (table 1). EMG recordings of 70 nocturnal enuresis episodes were obtained. In 44 cases a degree of pelvic floor activity was recorded in conjunction with voiding (before, during or after) and in 13 of them activity during micturition (less than 7 seconds after initiation of micturition) became evident. Fig-
To investigate the nature of the enuretic episode in MNE we used a noninvasive model of fluid provocation. The validity of the model can be substantiated by the fact that the excess fluid intake at bedtime led to episodes of enuresis rather than nocturia. Since the same model was previously used in healthy children of approximately the same age it is justifiable to compare the 2 studies. The response to fluid intake in the present study was different from that observed in healthy children receiving comparable amounts of water before bedtime, where by far the most common response was nocturia.7 Therefore, there may be differences between enuretics and normals regarding their awareness of and response to bladder filling during sleep. Polysomnographic studies of enuresis children led to analogous speculations demonstrating that these children share higher arousal thresholds12, 13 and the present study supports these findings. Electroencephalogram recordings were not performed in our study since evaluation of sleep patterns was beyond its scope, although the present model may be used for studies of the architecture of sleep in enuresis children. WHO defines the enuresis episode as normal and complete voiding.5 In our study significant amounts of residual urine were seen in nearly half of the nocturnal enuresis episodes and interestingly all but 2 of the participants experienced episodes with PVR. Nocturnal enuresis episodes with PVR were seen during baseline nights to the same degree as during the nights with fluid provocation, indicating that the degree of bladder emptying is apparently not influenced by polyuria per se. We found no differences in the number of enuresis episodes with incomplete emptying between those with and without polyuria. These striking observations support that incomplete bladder emptying is a common phenomenon in monosymptomatic
MONOSYMPTOMATIC NOCTURNAL ENURESIS AND ABNORMAL NOCTURNAL BLADDER EMPTYING
2565
FIG. 4. Examples of different pelvic floor EMG activity recorded during episodes of nocturnal enuresis. Arrows mark time of activation of enuresis alarm. A, presence of pelvic floor activity during micturition. B, no activity during voiding. C, complete EMG silence before, during and after nocturnal enuresis episode.
TABLE 2. Association between pelvic floor EMG activity and degree of bladder emptying during enuresis episodes Pelvic Floor EMG Activity during voiding phase No activity during voiding phase No EMG activity before, during or after enuresis episode
No. Significant PVR
No. Nonsignificant PVR
13 2 12
0 29 14
nocturnal enuresis occurring just as frequently as complete bladder emptying and refute the previous assumptions of enuresis being a complete voiding.3 An explanation for this finding could be that until now the enuresis episode had been evaluated using cystometric methods, which may provide accurate information on bladder dynamics during the night, but may not be the optimal method to study bladder emptying. The recordings of pelvic floor activity enabled us to elucidate the background behind incomplete bladder emptying. In all 13 cases with bursts of pelvic floor activity during voiding there was a significant PVR, corroborating previous findings of provoked enuresis in healthy children.7 It is plausible that during sleep children are able to interrupt micturition by activating the pelvic floor, and this involuntary withholding ability is likely to originate from the pontine micturition center. The absence of pelvic floor activity after initiation of micturition in 29 of 31 complete voidings indicates that the child was not able to suppress the micturition reflex. The EMG pattern seen in these cases is to some extent similar to that described for normal voiding at the awake state when no pelvic floor activity is seen after initiation of micturition.14 The fact that some children presented with both patterns of EMG activity during the same night could lead to the hypothesis that this fact is due to differences in the sleep stages in which enuresis occurs.12 Our findings are also in concordance with previous studies indicating a
general dysfunction of the brainstem maturation in patients with enuresis.15 In 26 cases we were unable to record any activity in the pelvic floor before and after initiation of the enuresis. Since an equal distribution of enuresis episodes with and without PVR was found in these cases, it can be speculated that this lack of pelvic floor activity is actually the result of insufficient EMG sampling. Similar observations were previously made of sleep cystometries in enuretic children with silent pelvic floor EMG.3 Since pelvic floor EMG recording during sleep is difficult, interpretations of silent EMG recordings should be made with particular caution. CONCLUSIONS
Fluid provocation is a valid noninvasive model for investigating the nature of nocturnal enuresis episode in children with monosymptomatic nocturnal enuresis. The induced polyuria leads to enuresis rather than nocturia, indicating failure of these children to awaken to a full bladder regardless of the type of enuresis. Incomplete bladder emptying is a frequent phenomenon in monosymptomatic nocturnal enuresis and is encountered to the same extent in children with and without polyuria. When pelvic floor activity is present during micturition it is associated with incomplete bladder emptying. Silent EMG patterns during micturitions similar to those seen during normal voidings in the awake state are generally associated with complete bladder emptying. The findings are in contrast to the current definition of monosymptomatic nocturnal enuresis as normal voiding with complete emptying. Therefore, reappraisal of the definition is suggested. REFERENCES
1. Fergusson, D. M., Horwood, L. J. and Shannon, F. T.: Factors related to the age of attainment of nocturnal bladder control: an 8-year longitudinal study. Pediatrics, 78: 884, 1986
2566
MONOSYMPTOMATIC NOCTURNAL ENURESIS AND ABNORMAL NOCTURNAL BLADDER EMPTYING
2. Forsythe, W. I. and Redmond, A.: Enuresis and spontaneous cure rate. Study of 1129 enuretis. Arch Dis Child, 49: 259, 1974 3. Norgaard, J. P.: Pathophysiology of nocturnal enuresis. Scand J Urol Nephrol, suppl., 140: 1, 1991 4. Hjalmas, K.: Urinary incontinence in children: suggestions for definitions and terminology. Scand J Urol Nephrol, suppl., 141: 1, 1992 5. Abrams, P., Khoury, S. and Wein, A.: 1st International Consultation on Incontinence, 1998 6. Norgaard, J. P., Hansen, J. H., Wildschiotz, G., Sorensen, S., Rittig, S. and Djurhuus, J. C.: Sleep cystometries in children with nocturnal enuresis. J Urol, 141: 1156, 1989 7. Kirk, J., Rasmussen, P. V., Rittig, S. and Djurhuus, J. C.: Provoked enuresis-like episodes in healthy children 7 to 12 years old. J Urol, 156: 210, 1996 8. Rasmussen, P. V., Kirk, J., Rittig, S. and Djurhuus, J. C.: The enuretic episode—a complete micturition from a bladder with normal capacity? A critical reappraisal of the definition. Scand J Urol Nephrol, suppl., 183: 23, 1997 9. Hansen, M. N., Rittig, S., Siggaard, C., Kamperis, K., Hvistendahl, G., Schaumburg, H. L. et al: Intra-individual variability in nighttime urine production and functional bladder capacity estimated by home recordings in patients with nocturnal enuresis. J Urol, 166: 2452, 2001 10. Koff, S. A.: Estimating bladder capacity in children. Urology, 21: 248, 1983 11. Coombes, G. M. and Millard, R. J.: The accuracy of portable ultrasound scanning in the measurement of residual urine volume. J Urol, 152: 2083, 1994 12. Wolfish, N. M., Pivik, R. T. and Busby, K. A.: Elevated sleep arousal thresholds in enuretic boys: clinical implications. Acta
Paediatr, 86: 381, 1997 13. Hunsballe, J.: Sleep studies based on electroencephalogram energy analysis. Scand J Urol Nephrol, suppl., 202: 28, 1999 14. Binnie, C. D., Fowler, C. J., Cooper, R., Mauguiere, F. and Prior, P. F.: Clinical Neurophysiology. Oxford: Butterworth-Heinemann, p. 4, 1995 15. von Gontard, A., Schmelzer, D., Seifen, S. and Pukrop, R.: Central nervous system involvement in nocturnal enuresis: evidence of general neuromotor delay and specific brainstem dysfunction. J Urol, 166: 2448, 2001 EDITORIAL COMMENT This is an excellent study of nocturnal enuresis using noninvasive technology so that recordings are as physiological as possible. These authors found that nocturnal enuresis episodes are associated with incomplete emptying. The WHO definition should be modified if other investigators are able to reproduce the study and the findings hold true for a larger number of patients. The clinical impact of this finding depends on the incidence of abnormal emptying in the population with nocturnal enuresis, which was not addressed in this study. Only the percentage of incomplete emptying among total episodes of enuresis for the group was noted. The mean post-void residual of the group was calculated. To assess severity and/or significance of abnormal emptying one would also like to know the post-void residual/functional bladder capacity. In summary, these authors found important characteristics of nocturnal enuresis by designing a study that should be reproducible and enable further investigation of this common pediatric problem. Jean G. Hollowell Fredrickson Outpatient Center Mechanicsburg, Pennsylvania