Other Miscellaneous Treatments to Enhance Bladder Emptying
In addition to those noted in the previous sections, there are a variety of other approaches that have been investigated to address the consequences of neurogenic bladder associated with SCI. These include the use of desmopressin acetate (DDAVP) as an adjuvant therapy to manage the effects of an overactive bladder otherwise refractory to conventional treatment such as nocturnal enuresis (i.e., night-time emission of urine) or the requirement for too frequent catheterizations. It is important to note that overactive bladder may be caused by other urologic abnormalities (e.g., benign prostatic hyperplasia, or UTI that can coexist with other consequences of neurogenic bladder secondary to SCI. Therefore, urodynamic evaluation is critical to assessing overactive bladder before adjuvant therapy is administered. If needed, DDAVP is a synthetic analogue of antidiuretic hormone most commonly administered by intravenous infusion for treatment of bleeding disorders. It can also be taken in the form of a pill or intranasal spray for reducing urine production as in the present application (Chancellor et al. 1994; Zahariou et al. 2007). DDAVP is thought to bind to V2 receptors in renal collecting ducts to increase water reabsorption.
Others have employed alternative approaches such as electroacupuncture (Cheng et al. 1998) or nerve crossover surgery / spinal root anastomoses (Livshits et al. 2004; Lin et al. 2008; Lin et al. 2009) to enhance recovery of bladder function. The utility of spinal root anastomosis in SCI came from groups rediverting the ipsilaterial C7 root to repair brachial plexus injuries with significant long-term effects of motor and sensory function of the upper extremities as a result of compensatory action of the other nerve roots (Gu et al. 2005). Since the brachial and sacral plexuses are organized similarly, the rediversion of local lower extremity nerve roots has been considered a possible, albeit highly invasive, treatment option.
Summarized Level 5 Evidence Studies
Nahm et al. (2015) reported that despite lower rates of bladder and prostate cancer in people with SCI vs people without SCI, bladder cancer related mortality is higher with more severe injuries. Sammer et al. (2015) suggested that screening strategies to prevent bladder cancers may be considered for people with SCI where those with more severe injuries are more at risk.
Discussion
Desmopressin Acetate
Zahariou et al. (2007) and Chancellor et al. (1994) conducted a pre-post (n=11) and a case series (n=7) investigation, respectively, to investigate the use of intranasal DDAVP as an alternative therapy to reduce urine production in the hopes of reducing nocturnal emissions or reducing the need for overly frequent catheterization during the day. In each case, DDAVP was employed as an adjuvant therapy in addition to standard therapies of anticholinergics and intermittent catheterization which had resulted in less than satisfactory results. With use of DDAVP just before bedtime, Zahariou et al. (2007) reported a statistically significant increase in urine production rate during the day (p<0.001) and a decrease in nocturnal urine production (p<0.001). After DDAVP treatment, participants had reduced or complete elimination of nocturnal enuresis (Chancellor et al. 1994; Zahariou et al. 2007). In addition, the proportion of persons requiring clean IC in the night while still maintaining continence was greatly reduced (Zahariou et al. 2007) and three individuals used DDAVP during the day at work and were able to achieve an additional 3.5 hours between catheterizations (Chancellor et al. 1994). These improvements persisted for a mean of 12 months. These small-scale studies provide only preliminary evidence and encourages further study, although DDAVP is in fairly widespread use for SCI-related neurogenic bladder.
Locomotor Training
A prospective controlled trial by Hubscher et al. (2018) studied the effects of locomotor training (LT) for improving motor outcomes post-SCI, specifically whether it can improve bladder, bowel and sexual function. Eight subjects used LT on a treadmill using body-weight support therapy, or LT and standing training. Filling cystometry documented significant increases in bladder capacity, voiding efficiency and detrusor contraction time as well as significant decreases in voiding pressure post-training relative to baseline. Questionnaires revealed a decrease in the frequency of nocturia and urinary incontinence for several research participants as well as a significant decrease in time required for defecation and a significant increase in sexual desire post-training. Authors concluded that these results suggest that an appropriate level of sensory information provided to the spinal cord, generated through task-specific stepping and/or loading, can positively benefit the neural circuitries controlling urogenital and bowel functions.
Electroacupuncture
Another adjunctive therapy that has been investigated is the use of electroacupuncture (EA). For example, Cheng et al. (1998) conducted a RCT (n=60) investigating the effectiveness of electroacupuncture administered in combination with conventional bladder management method (i.e., clean intermittent catheterization (CIC), tapping and trigger point stimulation) as compared to those not receiving electroacupuncture. Their primary outcome measure was the time to achieve bladder balancing which was defined as the time when: 1) the individual could easily pass adequate urine at low pressure, 2) residual urine of approximately 100 ml or less and 3) absent UTIs. Although employing a randomized, controlled design, some limitations (i.e., lack of blinding, concealed allocation or intent to treat) constrained the level of evidence assigned to this trial (i.e., Level 2). Regardless, those receiving electroacupuncture had a reduced time to achieve bladder balancing for both those with upper motor lesions (p<0.005) and lower motor neuron lesions (p<0.01). In addition, if electroacupuncture was started within three weeks of SCI, bladder balancing was achieved sooner than those who started after three weeks (p<0.005). Gu et al. (2015) also reported the superiority of EA+CIC effectiveness (vs CIC alone) in reducing residual urine volume (p<0.001) and frequency of CIC (p<0.001), increased voided volume (p<0.001), and promoting the balance of vesical function (p<0.05). Similarly, EA with bladder function training vs bladder function training alone is significantly more effective in increasing bladder volume and compliance, decreased residual urine volume, bladder pressure, rectal pressure, and detrusor pressure (p<0.05) (Xia et al. 2014). Modest improvements were also reported with bladder function training alone. The treatment group also had lower IPSS (International Prostate Symptom Score that describes various characteristics of urination) and better therapeutic efficacy (p<0.05) compared to controls.
Rectus Abdominus Detrusor Myoplasty (RADM)
Urinary bladder dysfunction in the form of acontractile/ hypocontractile bladder is very common after spinal cord injury and it may lead to recurrent urinary tract infection (UTI), stones formation, and deteriorating renal function. This is conventionally treated through the use of life-long clean intermittent catheterization (CIC) or an indwelling catheter (IC). For these individuals, another option is to use innervated skeletal muscle wrap around the bladder to augment detrusor function and voluntary evacuation of bladder. Agarwal et al. (2018) studied five individuals that underwent Rectus Abdominis Detrusor Myoplasty (RADM) to treat acontractile/hypocontractile bladder. These individuals were assessed by urodynamic study for post void residual volume (PVRV), detrusor pressure (Pdet), urine flow rate (Vmax), and bladder contractility index (BCI). Complete spontaneous voiding was achieved in all individuals. RADM elicits a statistically significant reduction in PVRV and statistically significant increase in urine flow rate, bladder contractility and detrusor pressure after six months. Another effect of treatment was all recurrent UTIs ceased in subjects.
Spincterectomy
External sphincterotomy (ES) in the treatment of SCI individuals with detrusor sphincter dyssynergia (DSD) is used to achieve low pressure urine storage and low pressure emptying of the bladder. By decreasing bladder outlet obstruction, reflex voiding can be performed with a lower bladder pressure, leading to more effective voiding, lesser incidence of UTI, preservation of upper urinary tract function, and reduction of autonomic dysreflexia (AD). Takahashi et al. (2018) conducted a long- term follow-up study after ES to determine if urodynamic parameters improved after the therapeutic procedure in male SCI individuals with DSD. Of the 37 SCI individuals studied, 27 are still managed with reflex voiding to a condom catheter (success group), while 10 needed to change their bladder management. Mean maximum bladder pressure (MBP) was maintained at a low level over 20 years after ES. However, neurogenic detrusor overactivity (NDO) gradually decreases over time, which might be one of the reasons for failure after ES.
Nerve Crossover Surgery – Spinal Root Anastomoses
Reports regarding microanastamosis to reinnervate the paralyzed bladder reveal recovery of neurogenic bladder dysfunction. These include surgical anastomosis of the intercostal nerve (Livshits et al. 2004, n=11), T11 nerve root (Lin et al. 2008, n=10), L5 nerve root (Xiao et al. 2003, n=15) or the S1 nerve root (Lin et al. 2009, n=12; Lin & Hou. 2013, n=9) to the S2 or S3 spinal nerve roots. Mean follow-up of individuals was between 2 to 3 years and restitution of bladder function was observed in the majority of individuals. Significant results were reported for pre and post-surgical findings including reduced bladder capacity with increased urine volume under increased force of detrusor contractions and increased voiding pressure. There was also reduced residual urine volume and both detrusor tone and sphincter resistance were increased. Results from individual subjects in Livshits et al. (2004) were presented for each of these showing consistency across these measures although statistical analysis techniques were inappropriate consisting of individual Wilcoxon signed rank tests for each variable. Individual self-report measures showed increases within a few months following surgery. Similar findings were evident in 100%, 67%, 71%, and 78% of individuals undergoing T11, L5, and S1 microanastamosis, respectively (Lin et al. 2009; Xiao et al. 2003; Lin et al. 2008; Lin & Hou 2013). Full recovery of renal function and an absence of UTI was observed at follow-up (i.e., 6-18 months). Of the 7 of 9 individuals in the Lin and Hou (2013) study that recovered full bladder storage and voiding function, the return of bladder sensation (able to sense full bladder and desire to void) also accompanied the lack of nocturnal urinary incontinence by 8-12 months postoperatively. Important considerations of this surgical approach are that it is far more invasive than other approaches (i.e., indwelling catherization); and some individuals do not show any improvement postoperatively. In particular, accidental voiding may be triggered by unintentional dermatomal stimulation or Achilles tendon stretch. Furthermore, considering the potential for up to 30% failure rates and serious side effects (i.e. neuromas) this invasive procedure must be weighed cautiously against other approaches to treatment of bladder dysfunction. However, more recently, 2 small, independent pre-post studies confirmed that the Xiao procedure for intradural anastomosis to improve bladder function, was ineffective (Sievert et al. 2016, Rasmussen et al. 2015).
Bladder Cancer
Contrary to morbidity rates for many secondary conditions in spinal cord injured individuals, the overall incidence of bladder and prostate cancer is reported to be lower by 12 and 33%, respectively for a cohort of people with SCI vs non-SCI (Lee et al 2014; n=27,2005). Although Nahm et al. (2015, n=45,486) did not confirm lower rates of bladder cancer in people with SCI, they did report that people with SCI are not at increased risk compared to people with SCI. However, this large US database did reveal increased bladder cancer mortality in people with more severe injuries (e.g. AIS A, B, C) with AIS D individuals, who typically do not have problems with neurogenic bladder or UTIs, having the risk of mortality as the general population. This group did not observe an increased mortality rate in ventilator dependent or high cervical injury individuals and postulated that their overall shortened life expectancy might have bypassed the development of bladder cancer. These results advocate for screening strategies to identify at-risk groups with contributing factors for bladder cancer related deaths. Urethro-cystoscopy and/or bladder washing cytology and histology are relevant screening strategies that report 10% and 5%, respectively, identification rates in individuals with at least 5 years’ history of neurogenic lower urinary tract dysfunction (Sammer et al. 2015).
Bladder Stones
Compared to the general population, individuals with SCI have a higher risk of bladder stone formation (Chen et al. 2002; Bartel et al. 2014). Secondary complications arising from urinary stasis, hypercalciuria due to immobilization, and long-term catheter use are all contributing factors to the higher prevalence of bladder stone formation in people with SCI. Bartel et al. (2014) associated bladder stones in individuals using suprapubic catheters (SPC, 11%), transurethral catheters (TC, 6.6%), intermittent catheterization (IC, 2%) and reflex micturition (RM, 1.1%). The time interval to bladder stone development for TC, SPC, IC, and RM was 31, 59, 116 months and 211 months, respectively. Similarly, recurrence rates were 40, 28, 22 and 0%, respectively. Conversely, time to recurrence for the TC group was the longest at 31 months and 26 and 14 months for IC and SPC groups, respectively. Once a stone required treatment, Eyre et al. (2015) reported overall complication rates ranging from 0% to 11% to 25% following washout, stone punch and electrohydraulic lithotripsy (EHL) techniques, respectively. Combining stone punch and EHL yielded significantly higher overall rate of complications (38%, p=0.046), which was further exacerbated when these combined procedures were carried out on individuals with cervical-level injuries (p=0.032). Having a complication, a combined procedure, and age contributed to significantly longer lengths of stay (p<0.001) than when stone punch alone is chosen.
Other
Endoscopic application of bulking agents is a treatment option for vesicoureteral reflux (VUR) in individuals with chronic SCI. Virseda et al. (2014) found that the greatest success was achieved after neurogenic detrusor overactivity (NDO) was first eradicated. Otherwise, individuals with NDO experienced a high failure rate even though reflux was independent of involuntary detrusor contraction. Although individual age, presence of stress urinary incontinence (SUI), bilaterality were also thought to be predictive factors of success, multivariate analysis revealed that only degree of reflux and NDO were independent factors affecting success rate for anti- reflux procedures.
Conclusion
There is level 1a evidence (from three RCTs: Cheng et al. 1998; Xia et al. 2014; Gu et al 2015) that supports using electroacupuncture to significantly improve bladder function, when combined with conventional methods of bladder management.
There is level 2 evidence (from one prospective controlled trial: Hubshcer et al. 2018) that the use of locomotor training may increase bladder capacity, voiding efficiency and detrusor contraction time, as well as significant decreases in voiding pressure post-training.
There is level 4 evidence (from one pre-post study and one case series study: Zahariou et al. 2007; Chancellor et al. 1994) that intranasal DDVAP may reduce nocturnal urine production with fewer night-time emissions and also may reduce the need for more frequent catheterizations in persons with SCI with neurogenic bladder that is otherwise unresponsive to conventional therapy.
There is level 4 evidence (from one pre-post study: Agarwal et al. 2018) that Rectus abdominis detrusor myoplasty (RADM) appears to be a promising option in a individual with acontractile/ hypocontractile bladder to restore the bladder function.
There is level 4 evidence (from one pre-post study: Takahashi et al. 2018) that Mean maximum bladder pressure (MBP) is preserved at a low level following external sphincterotomy (ES), however neurogenic detrusor overactivity (NDO) gradually decreases over time over the years after ES, which would be one of the causes of failure of ES.
There is level 4 evidence (from three pre-post studies: Lin et al. 2009; Lin et al. 2008; Lin & Hou 2013) that nerve crossover surgery (anastomosis of T11 or S1 to S2-S3 spinal nerve roots) may result in improved bladder function in chronic SCI.
The balance of level 4 evidence (from three pre-post studies: Xiao et al. 2003 (positive results); Rasmussen et al. 2015 (negative results); Sievert et al. 2016 (negative results)) suggests that the Xiao procedure (L5-S3 ventral root anastomosis to establish a new reflex pathway) is ineffective for improving bladder function).
There is level 2 evidence (from one cohort study: Lee et al. 2014a, n=27,2005) that reported a lower rate of bladder and prostate cancer in people with SCI vs people without SCI.
There is level 2 evidence (from one cohort study: Eyre et al. 2015) that reports higher complication rates for combined bladder stone procedures vs stone punch alone.
There is level 4 evidence (from one case series study: Bartel et al. 2014) suggesting that bladder stone development occurs with suprapubic, transurethral, intermittent catheter use in descending frequency with reflex micturition have the lowest occurrence.
There is level 3 evidence (from one case control study: Virseda et al. 2014) suggesting the eradication of NDO before proceeding with endoscopic application of bulking agents to treat VUR with a higher success rate.
