Hypothesis / aims of study
This is the first study on the pathogenesis of primary monosymptomatic nocturnal enuresis (PMNE) by combining functional MRI (fMRI) and ambulatory urodynamics monitoring (AUM). PMNE is a heterogeneous disorder, which remains a difficult condition to manage due to lack of knowledge on pathophysiological mechanisms. Functional MRI detects blood oxygen level–dependent (BOLD) variation in the MRI signals associated with changes in neuronal activity of the brain. With the development of BOLD-fMRI, this technique has been gradually applied to the study of pathogenesis of PMNE as a non-invasive neurologic examination. In addition, AUM has become an indispensable examination method for the assessment of lower urinary tract dysfunction because it is more physiological than conventional urodynamics (CUD). The objective of this study was to investigate the central abnormality and nocturnal bladder dysfunction in PMNE by combining the resting state fMRI and AUM, thus providing an objective basis for correct diagnosis and treatment.
Study design, materials and methods
There were two groups of 37 children: the PMNE group (20 males, 17 females) and the control group who needed surgery because of upper urinary tract diseases and with normal lower urinary tract function detected by CUD (19 males, 18 females). The diagnosis of PMNE complied with the diagnostic criteria established by the International Children’s Continence Society (ICCS). The mean age of the children with PMNE was 11.3±4.1 years, while the average age of the normal controls was 11.1±2.9 years (P>0.05). A detailed case history, 3-day voiding diary, BOLD-fMRI scan, CUD, and AUM were performed in the PMNE group, respectively. Resting state BOLD-fMRI scan was performed in all children of the PMNE group and 13 children of the control group (7 males, 6 females).
The ALFF value of the left medial frontal gyrus of PMNE decreased and the ReHo value of the left superior occipital gyrus increased compared with those of the control group (Figure 1). The maximum voiding volume (MVV), nocturnal urine output (NUO), and nocturnal bladder capacity (NBC) of children with PNME were 303.11±87.48ml, 568.65±208.48ml, and 217.43±81.53ml, respectively. The incidence of MVV reduction, nocturnal polyuria, and NBC decrease was 24.32%, 56.76%, and 64.86%, respectively. The parameters of CUD and AUM for the PMNE and control group were compared (Table 1). In the PMNE group, 29 children (78.38%) showed detrusor overactivity (DO) under AUM, which was significantly more (P<0.05) than that under CUD (16 children, 43.24%). In children with DO detected by both CUD and AUM, the maximum detrusor pressure when DO was occurring during AUM was significantly higher than that during CUD (19.56±6.01 cmH2O vs. 14.38±3.07 cmH2O, P<0.05).
Interpretation of results
Arousal dysfunction caused by the central nervous system plays a vital role in the pathogenesis of PMNE. Resting state fMRI focuses on low-frequency oscillations in spontaneous brain activity, and ALFF and ReHo analyses are two common parameter analysis methods used to investigate the characters of local intrinsic activity in fMRI studies. The left medial frontal gyrus belongs to the prefrontal cortex, which is one of the most active brain regions in the frontal lobe. The left superior occipital gyrus is a part of occipital lobe. We assumed that the left hemisphere of children with PMNE possibly cannot control voiding properly in nature. However, this disorder could be compensated by the normal function of right hemisphere in the daytime when they are awake but could not during sleep, leading to bed-wetting. Therefore, the results of this study suggest that the left medial frontal gyrus and superior occipital gyrus may play a crucial part in the pathogenesis of arousal disorder in PMNE, which is expected to be a new target for the treatment.
Substantial evidence supports the hypothesis that MNE is caused by a mismatch between NUO and bladder capacity. In this study, the results of voiding diary showed that increased NUO occurred in 56.76% of children with PMNE. The large NUO in children with PMNE seems to be caused mostly by the deficiency of nocturnal arginine vasopressin. The decrease in the NBC would lead to the increase in urination frequency at night. If children are accompanied by arousal disorder, they cannot urinate at an awake state, which will lead to enuresis. Although some children also had a decrease in MVV at different degrees during the day, most children had a decrease in NBC while MVV was normal in the daytime. Therefore, it is important to take into consideration both MVV and NUO at wet days when evaluating the storage function of bladder from voiding diary, especially for refractory cases.
AUM provides the most physiologic simulation of bladder filling. Previous studies have shown that many children with PMNE have bladder dysfunction, which is mainly manifested as DO at night. In this study, we found that 78.38% of children with PMNE showed DO at night according to the results of AUM. AUM has been showed to be more sensitive than traditional urodynamics in diagnosing DO, which may lead to a higher detection rate. Therefore, AUM has a clear diagnostic value for children with underlying DO which is not detected by CUD, and could provide theoretical basis for the selection of treatment options.
The maximum detrusor pressure detected by AUM during the urination period was significantly higher than that detected by CUD, and the reason was unclear. We assume that the difference may be mostly related to different bladder filling modes and media. During AUM, the bladder is filled at a physiological state, while the bladder is filled with normal saline at room temperature at a certain perfusion rate during CUD. In this case, the contractile force of detrusor is weakened when overfilled artificially.