To our knowledge, this is the first study to objectively compare the baseline profile of ANS activity and responses to bladder filling in children with or without spina bifida using spectral analysis of cardiovascular signal variability methodology. Several findings in our study are noteworthy. First, the baseline profile of HRV was altered in spina bifida patients in terms of decreased values related with the peripheral nervous system (RMSSD, pNN50, HF) and increased LF/HF ratio representing sympathetic dominance. The response to bladder filling also significantly differed between the two groups, most pronounced in the LF/HF ratio (increasing value in the control group vs decreasing value in the spina bifida group with bladder filling). These results provide an explanation of the underlying neuropathology in spina bifida.
There are a variety of urological consequences depending on the severity of the fusion abnormality and location of the lesion. An upper motor neuron lesion with detrusor overactivity and detrusor sphincter dyssynergy are most likely to develop, but an acontractile detrusor and sphincter denervation are also seen as a result of spinal cord tethering.9,10 The mainstay in treatment of spina bifida is still combination of pharmacological agents and clean intermittent catheterization, which has had limited success.11 Current treatment strategies have focused on preventing the consequences of neurogenic bladder rather than trying to understand the disease, therefore the understanding of the disease has not yet improved.
Since the first report of changes in HRV by Hon and Lee,12 HRV has been used extensively as a quantitative marker of ANS activity. Previous studies demonstrated that ANS dysfunction proven by HRV reflects the underlying pathology of LUTs.5,8 The most frequently studied LUTs associated with HRV is overactive bladder (OAB), which is controversial as the results, as well as study settings, of how ANS differs from healthy controls were heterogenous. Hubeaux et al. reported a predominance of parasympathetic activity with the bladder emptied and a preponderance of sympathetic activity at the end of bladder filling in women with OAB syndrome.13 Choi and Kim observed a decrease in HRV indexes, including HF, SDNN, RMSSD, in women presenting with OAB compared to healthy women.14 In children with bladder bowel dysfunction, HF was significantly lower than healthy controls at baseline.15
In healthy subjects, LF/HF ratio showed a stable sympathovagal balance until first desire to void, while the balance demonstrated a shift towards sympathetic activation before strong desire to void.4 This response is thought to be caused by a similar mechanism to the vesicovascular response that is mediated by sympathetic nerves, such as the hypogastric nerve.16 Unlike previous studies, LF/HF ratio increased until first desire to void and continued to rise until the end of filling in our study. This result may be due to the younger age group in our study not being capable of expressing exact bladder sensation and also the wide variation of HRV value. During bladder filling, contrary to the control group, only HF increased without increasing LF in the spina bifida group, resulting in a decrease in LF/HF ratio. These results suggest ANS dysfunction, predominantly a sympathetic ANS dysfunction, in spina bifida. Given that the thoracolumbar sympathetic efferent pathways in the hypogastric and pelvic nerves induce an inhibition of detrusor muscle and an excitation of the bladder base and urethra, the alterations observed in sympathetic activity during bladder filling may lead to a sensation of urgency and a problem in urine storage. In our study, neurogenic detrusor overactivity (NDO) was seen in only 4 patients (36.3%); however, on past urodynamic studies, NDO was observed in all except 1 patient. These urodynamic results may be associated with the decreased LF/HF ratio during bladder filling.
In addition, SDNN in time domain was significantly increased with bladder filling in the control group, whereas in remained unchanged in spina bifida patients. Given that SDNN represents overall HRV,17 the unchanged value of SDNN in spina bifida may be due to decreased neurotransmission of ANS during bladder filling. With extrapolation from the enteric nervous system, which has similar nerve distribution as the bladder, neural loss and decreased nerve fiber density in the myenteric plexus was seen in spina bifida patients, which correlated with severity of bowel dysfunction.18 These alterations may be caused by reaction to disrupted extrinsic innervation, resulting in trans-neuronal degeneration. Therefore, we infer that these evidences may be related to an overall decreased HRV value during bladder filling in spina bifida, but they cannot explain the sympathetic predominance at baseline.
Recently, autonomic cardiovascular function was evaluated in wheelchair-using children with MMC, and RMSSD at rest were reduced compared to the control group, which agrees with our results of reduced RMSSD, pNN50, and HF in the spinal bifida group at baseline.19 The pathology underlying reduced vagal tone and increased LF/HF ratio in spina bifida patients is uncertain. In patients with thoracic spinal cord injuries, higher heart rates and reduced vagal tone has been documented.20 This may reflect compensation for decreased stroke volume and compensatory reductions in vagal tone to maintain autonomic balance.21,22 Deteriorating vascular properties (small diameter, low flow, and high shear stress) were present in patients with spina bifida23, and these results suggest that decreased vagal tone and sympathetic predominance in spina bifida may occur via similar mechanism demonstrated in spinal cord injury.
The main limitation of this study was the small number of subjects, therefore, HRV analysis was not performed for each subtype according to urodynamic study. Considering the large deviation of baseline HRV, a larger study is required to confirm our results. The second limitation is HRV measurements in our study were performed with a non-medical Bluetooth device, not with conventional ECG. However, recent studies have demonstrated that Bluetooth devices have provided an acceptable agreement for the measurement of HRV when compared with ECG. Therefore, the measurement method in this study has validity.24,25 Although other criteria could be considered to see the change in HRV in terms of time, it is difficult to divide periods based on a specific time because each patient has different filling time inherent to their bladder capacity. Patients with spina bifida often lose their sense of bladder and demonstrate underactivity of bladder, which leads confusion in deciding proper point of each period. Despite these limitations, the criteria we applied to divide each period could be suboptimal method to observe the trends of HRV changes on bladder filling in both of control and spina bifida. Another concern is that HRV may be affected by emotional stress caused by the artificial setting of the study, however, the same setting was applied in both groups and the examination was conducted with sufficient time to adapt. Another limitation may be that the control group consisted of children with VUR who may have abnormal bladder dysfunction that may be related to HRV, although this has not been studied.
At baseline, HRV parameters representing PNS activity are decreased in children with spina bifida compared to control group. During bladder filling, parasympathetic activity was relatively increased with a fixed sympathetic activity in spina bifida while control group demonstrated a shift in sympathetic/parasympathetic balance towards the sympathetic component. These results may be related to underlying neuropathology caused by spina bifida, which could be used to better understand and manage spina bifida.