Curr Bladder Dysfunct Rep (2013) 8:289–296 DOI 10.1007/s11884-013-0200-0

NEUROGENIC BLADDER (C POWELL, SECTION EDITOR)

Voiding Dysfunction and Upper Tract Deterioration after Spinal Cord Injury Sara M. Lenherr & Anne P. Cameron

Published online: 29 August 2013 # Springer Science+Business Media New York 2013

Abstract This is a review of the most current literature on the evaluation and management of the urinary system after spinal cord injury (SCI). Spinal cord injury virtually always results in some degree of neurogenic bladder (NGB) dysfunction. While it is widely accepted that NGB dysfunction is associated with an increased risk of urologic complications, consensus regarding screening for those complications, and medical or surgical management is not widely accepted. Regarding screening for complications, an annual renal ultrasound is an appropriate screening test to assess for renal pathology including stones. General guidelines for urodynamic evaluation in patients with SCI were recently published and do not explicitly recommend routine testing. Regarding NGB complications, neurogenic bladders are most prone to urinary tract infections and stones. Medical, equipment and surgical options are all aimed at decreasing the risk of these complications in SCI patients. Keywords Spinal cord injury . Neurogenic bladder . Catheter . Intermittent catheterization . Urinary tract infection . Nephrolithiasis . Renal Abbreviations: CIC CKD CMG EMG GFR MDRD

clean intermittent catheterization chronic kidney disease cystometrogram electromyography glomerular filtration rate modification of diet in renal disease

S. M. Lenherr (*) : A. P. Cameron Department of Urology, Division of Neurourology and Pelvic Reconstructive Surgery, University of Michigan, 1500 E. Medical Center Drive 3875 Taubman Center, SPC 5330, Ann Arbor, MI 48109-5330, USA e-mail: [email protected] A. P. Cameron e-mail: [email protected]

NGB PCNL SCI UDS UTI

neurogenic bladder percutaneous nephrolithotomy spinal cord injury urodynamics urinary tract infection

Introduction Spinal cord injury (SCI) can lead to devastating neurologic and urologic complications. Modern bladder management techniques and medications have reduced the morbidity and mortality associated with neurogenic bladder (NGB), but urologic complications are still all too frequent. Large evaluations of SCI cohorts are helping providers understand the trends in SCI care and complications. The Model SCI database contains 24,762 patients who sustained a traumatic SCI between 1973 and 2005 [1]. Urologic complications (pressure ulcers, kidney stones) and hospitalizations were evaluated in this cohort and compared based on type of bladder management. In this population, indwelling catheters were associated with higher rates of urologic complications. In order to reduce the rate of urologic complications associated with SCI, research has looked at patient knowledge to help understand the role the patient takes in their own healthcare. In a single Level 1 trauma center, 214 SCI patients were assessed regarding knowledge about pressure sores and bladder management [2]. At the time of admission to a SCI special rehabilitation center, the average knowledge score as assessed by a novel questionnaire, was 5.4 (scale 0 least-20 maximum) and improved to 11.2 at the time of discharge. Patients indicated that their primary source of information was the rehabilitation physician (77.6 %) while they were in the rehabilitation hospital. Of note, the Internet was the fourth most important information source in this group of patients, and use of the Internet increased at 30 months after discharge

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(from 21.2 % to 39 %). Further research into patient education and transmission of medically sound information could greatly empower this population. Urodynamics Because the level of spinal cord injury does not reliably predict bladder function, urodynamic (UDS) testing is a mainstay in the management and diagnosis of neurogenic voiding dysfunction. The American Urological Association has recently created guidelines on UDS studies in adults [3••]. In summary, their recommendations for neurogenic bladder are: “Clinicians should perform post-void residual assessment (either as part of complete urodynamic study or separately), a complex cystometrogram (CMG), pressure flow analysis and electromyography (EMG) during the initial urological evaluation of patients with relevant neurological conditions (e.g., spinal cord injury, myelomeningocele) and as part of ongoing follow-up when appropriate. Clinicians may perform fluoroscopy when available.” Of note, the evidence strength of the references that the panel utilized to create these recommendations was grade B or C. Patients who regain the ability to walk after an incomplete SCI are often perceived as having a less severe neurogenic bladder, however recent investigations have shown that this is not the case. Belluci, et al. compared UDS findings in 60 patients with new SCI who either were ambulatory (17 patients) or wheelchair bound (43 patients) [4]. There was no difference in unfavorable urodynamic parameters in the two groups including detrusor sphincter dyssynergia, poor compliance, detrusor overactivity and high pressure storage. These and other authors recommend that patients receive the same urological assessment and follow-up regardless of ambulatory status after SCI [5]. Given the risk of instrumentation involved with UDS, investigators have evaluated non-invasive means to measure bladder function [6]. Bladder wall thickness on ultrasound was compared to urodynamic parameters in 60 patients with SCI. The authors found that a thickness of 0.97 mm or less could predict with 91.7 % sensitivity and 63 % specificity the absence of risk factors such as poor compliance and high leak point pressure for upper tract damage. This technique could not however predict detrusor overactivity which is an important finding hence this technique thus far cannot replace traditional UDS. Renal Failure In addition to chronic health conditions that afflict the normal aging population, adults with SCI have many risk factors for chronic kidney disease such as a high rate of urinary infections, bladder dysfunction and nephrolithiasis [7••]. However, our understanding of chronic kidney disease (CKD) in this

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population is hampered due to the inaccuracy of the currently used estimate of GFR in the SCI population. SCI individual’s GFR is overestimated due to their very low percentage of muscle mass. A correction factor for the Modification of Diet in Renal Disease (MDRD) was recently developed and validated in SCI [8]. Using this formula, Fischer et al. estimated the prevalence of CKD in a population of Veterans with SCI [7••]. Of the 9333 Veteran’s identified 35.2 % were found to have CKD (GFR<60 ml/min/1.73 m2) utilizing the modification, but only 10.2 % were found to have CKD with the uncorrected formula. Risk factors for CKD were older age, white race, non-traumatic etiology of SCI and, not surprisingly, other chronic health conditions (hypertension, diabetes, coronary artery disease) traditionally associated with CKD. Finally, in a systematic review of urological surveillance after SCI, articles on upper tract abnormality surveillance were reviewed [9••]. Eleven articles evaluated the use of ultrasound compared to other imaging modalities. Ultrasound was excellent at detecting calyceal dilatation, hydronephrosis and renal masses, but was not as good as voiding cystourethrogram at detecting vesicoureteric reflux. Renal ultrasound had a sensitivity of 0.96 and specificity of 0.90 for detecting hydronephrosis as compared to renal scan with sensitivity and specificity of 0.91 and 0.84, respectively [10]. Renal ultrasound was also more sensitive than renal scans at detecting structural abnormalities of the kidney. Renal scans were evaluated in 11 articles and were superior to intravenous pyelogram and voiding cystourethrogram at detecting poor renal function, but their utility in patients with normal ultrasounds was not demonstrated and they should be reserved for those with abnormal ultrasounds or deteriorating serum creatinine. Serum creatinine was very poor at determining GFR in one article however 24-hour urine creatinine clearance was accurate when the correct equation was applied, but not very practical. Stones Spinal cord injured individuals are at increased risk of upper tract urolithiasis compared to the general population. Their risk of stone formation is 7-20 % over 8-10 years with a high rate of stone recurrence [11]. These stones have a variety of etiologies, but early demineralization of bone due to immobility and the resulting high serum calcium are significant causes especially in the first several months after injury. Recurrent urinary tract infections are very common in people with SCI and this is the other predominant cause of renal stones in this population. Other biochemical abnormalities do exist in individuals with SCI such as hypocitraturia, hyperuricemia, and low levels of stone formation inhibitors, but these urine abnormalities do not seem to be the cause of stones since they occur equally in SCI patients with and without renal stone formation [12].

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There is sparse research written on the composition of stones in SCI. In a cohort of 33 patients with musculoskeletal anomalies (33 % SCI) undergoing percutaneous nephrolithotomy (PCNL), 18.4 % of patients had struvite stones compared to 6.2 % in a control group [12] challenging the current notion that most stones are infection-related. Most of these stones were not infection related with 52 % hydroxyapatite, 10.5 % calcium oxalate and 7.9 % brushite. On 24hour urine the most clinically significant difference between cases and controls was a very high urine pH (6.83 vs. 6.05 in controls) explaining the high incidence of calcium phosphate stones. Perhaps with better urological care the stone composition in SCI is shifting so that the majority of stones are now metabolic in origin instead of the infection related stones of the past [13•]. Surprisingly little has been written on ureteroscopic treatment of upper tract stones in SCI patients with most of the published literature presenting series of conservative treatment, PCNL or extracorporeal shock-wave lithotripsy predating current fiber optic technology [13•]. With advances in endoscopic instrumentation and the widespread availability of flexible ureteroscopy, challenges such as patient positioning preventing stone access is no longer as significant of a barrier to stone management. The first contemporary publication on the surgical outcomes of laser lithotripsy in SCI by Wolfe et al. demonstrated that this procedure is effective at removing clinically significant stones, however with a higher complication rate than the general population [14]. They followed 29 SCI patients at a Veterans Affairs Hospital who had a total of 67 ureteroscopies over a 15 year period (19952010). This is a complex cohort with 85 % managing their bladder with an indwelling catheter and on average 18-years post injury. Complete stone clearance (clearance of all stones greater than 4 mm) after the first procedure was only 34 %. And, of the 44 cases with residual stones, half were attributed to technical difficulties. Intraoperative complications were rare with 1.5 % ureteral perforation and no problems with autonomic dysreflexia likely due to the high usage of regional anesthesia (63 %) [14]. However, perioperative complications were common at 30 % with the most common complication being urosepsis in 12 of 67 cases. Other severe complications included respiratory failure (4.5 %) and there was one death of combined sepsis and respiratory failure. Factors associated with an increased rate of complications included lack of preoperative stent, COPD and incomplete SCI. Of cases 72 % required a repeat procedure on the ipsilateral renal unit to clear residual stones. Percutaneous nephrolithotomy is still a useful approach to large stones that warrants mention. In a single center series, Knox et al. reported clinical outcomes after PCNL in 47 patients with SCI (n=26), spina bifida (n=16) or other causes of neurogenic bladder [15]. Among the cohort, 40 % had an indwelling or external catheter, 28 % had a urinary diversion,

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and 19 % performed clean intermittent catheterization. In total 66 PCNL procedures were performed. As would be expected in such a cohort of complex NGB patients, 93 % of cases had preoperative positive urine colonization and 37 % of patients had infection-related struvite/carbonate apatite stone composition. Given the complex nature of these patients it is not surprising that there was a high complication rate: severe complications included sepsis (n=8), prolonged intubation (n=4), ARDS, hemothorax, AV fistula formation, extremity amputation from prolonged vasopressors and death each in one patient. Predictors of adverse events or need for repeat stone surgery included the need for multiple access, upper pole access, and larger stone size. Neurological disease, bladder management method and stone composition did not affect complications. Patients with positive urine cultures were aggressively treated with culture-specific antibiotics for a week preoperatively and during their hospitalization which the authors attribute to their low sepsis rate of 19 %. One obstacle to managing stones in patients with SCI is the lack of guidelines on when and how to screen in this high risk population. In a systematic review of urological follow up after SCI, nine articles evaluated screening for stones in persons with SCI [9••]. Ultrasound had good sensitivity for both bladder and upper tract stones in six articles. Ultrasound was also superior to renal scan. Plain x-ray film of the kidneys ureters and bladder (KUB) was very poor with only 14-54 % sensitivity for detecting bladder stones and less than 50 % of the renal area visible. Other modalities such as intravenous pyelogram and CT scan were sensitive at detecting stones, but entailed the use of radiation and/or intravenous contrast hence their usefulness as a screening tool is not optimal. The authors determined that an annual renal ultrasound is an ideal screening tool both for upper tract anomalies and urolithiasis. Urinary Tract Infections and Catheters Clean intermittent catheterization (CIC) is considered the method of choice for NGB management, if feasible by the patient or caregivers. Urinary tract infections (UTIs) are the most common complication of any form of catheterization. Wyndaele et al. reviewed the literature pertaining to CIC and the risk of UTI [16••]. They reconfirmed that while UTI is a major complication of CIC, conclusions about risks and etiology are limited because of the lack of a uniform UTI definition. To reinforce the lack of data, a Cochrane Collaboration review was recently updated pertaining to catheter use in patients with NGB [17]. None of the 400 studies identified met inclusion criteria to qualify for analysis, thus no recommendation could be made about the superiority of CIC, chronic indwelling catheter, external sheath catheter or timed voiding in the management of NGB. UTIs are the most common infection in patients with SCI however, preventative strategies such as long term antibiotics

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and local antimicrobial control techniques have been up until recently ineffective in eliminating catheter-related UTIs [18]. Darouche et al. performed a multicenter randomized controlled trial of bacterial interference to prevent UTIs in patients with NGB. Patients with NGB were randomized to receive either Escherichia coli HU2117 or sterile saline inoculation directly into the bladder. E. coli HU2117, a derivative of E. coli 83972, has lost the genetic potential for expressing Pspecific adherence. While only 38 % of the patients achieved bladder colonization, in those patients that were colonized, there was more than a two-fold reduction in the incidence of UTI in those patients colonized with E. coli HU2117 versus the control population (29 % versus 70 %, respectively). Prior trials by other groups have attached E. coli 83972 directly to catheters with evidence that it did decrease the UTI rate in patients performing CIC from 2.27 UTIs per patient year to 0.77 UTIs per patient year with successful colonization [19]. UTI was defined as ≥105 cfu ml-1 and pyuria (>10 WBC per high powered field) plus ≥1 sign/symptom of UTI. But, this method of inoculation was similarly cumbersome, requiring treatment with culture specific pre-insertion antibiotics for 7 days, a wash-out period for 3-4 days and then placement of an indwelling catheter (inoculated with E. coli 83972) for 3 days. This still only resulted in a 55 % inoculation rate (≥102 cfu ml-1) for >3 days after the catheter was removed. This seems to be a promising area of research to combat one of the most challenging aspects of care in patients with SCI. While a complete review of the diagnosis and management of catheter-associated UTIs is beyond the scope of this chapter, current Infectious Diseases Society of America practice guidelines are comprehensive and specifically do not recommend screening for asymptomatic bacteriuria in asymptomatic patients who use either chronic indwelling or intermittent catheterization [20••]. In light of the new variety of catheters available, a review of catheter materials was published in 2013 [21]. Eight studies were included in the systematic review and most patients in the studies were males after SCI. There was no difference between hydrophilic and sterile non-coated catheters as measured by mean monthly UTIs or total UTIs at 1 year. Another group conducted a meta-analysis to determine the impact of hydrophilic catheters on UTI rate in SCI patients and found a decreased rate of UTI and hematuria with the use of hydrophilic catheters [22]. Unfortunately, the quality of the analysis was limited by poor definitions of hematuria and UTI. More work is needed to see if catheter material truly effects urologic complications. Two groups published data pertaining to a new 30-cm-long telescoping hydrophilic-coated male intermittent catheter (SpeediCath Compact Male; Coloplast A/S , Humlebæk, Denmark) and demonstrated that this catheter was discreet, worked effectively and was not inferior to the standard-length product with respect to comfort in SCI

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patients [23, 24]. Of note, both studies were funded by the catheter’s manufacturer. Urologic Medical Management in SCI Patients There is a paucity of publications on the use of medications in patients with SCI due to the boom in Onabotulinum toxin A use in the management of NGB. Onabotulinum toxin A in the NGB is addressed in a separate chapter. Available medications frequently used in patients with NGB secondary to SCI include anticholinergics, imipramine and alpha-blockers [25]. Anticholinergics are first line medical therapy for neurogenic detrusor overactivity and poor bladder compliance [26, 27]. Several anticholinergics are available, with different doses, immediate release versus long acting formulations and modes of delivery. There is no demonstrated superiority between the most studied medications: oxybutynin, propiverine and trospium chloride [27]. The remaining anticholinergics are less well studied in the NGB population. In general, anticholinergics show a dose-response relationship with decreased maximum detrusor pressure and an increase in the maximum cystometric capacity. β3-adrenoreceptor agonists are a new class of medications to modulate bladder function. Mirabegron is the first commercially available medication in this class and has not yet been studied in patients with SCI and NGB [28]. Initial studies in patients with overactive bladder syndrome have just been published and we anticipate future studies to evaluate the efficacy and safety in the SCI patient population. Given the novel mechanism this medication may be a candidate for combination therapy with anticholinergics. Surgical Treatment Urinary incontinence is very troublesome for patients with spinal cord injury since they often do not sense the leakage episode, are at very high risk of decubitus pressure ulcers as well as social isolation. There are two basic causes of incontinence: an incompetent outlet from intrinsic sphincter deficiency or an inability of the bladder to store urine due to detrusor overactivity or poor compliance. An incompetent outlet is often protective of the upper tract since the leak point pressure is low. Therefore, one must ensure that underlying poor bladder compliance or overactivity is also concomitantly treated when treating the outlet to avoid the dangerous combination of high pressures in the bladder and a competent outlet putting the kidneys at risk. Intrinsic sphincter deficiency, especially in the female population, has been traditionally treated with an autologous pubovaginal sling. In a retrospective review of 33 women with neurogenic bladder, preoperatively 82 % had severe incontinence (>5 pads per day) and all performed CIC [29]. In addition, nine had low bladder pressures at baseline, seven had bladder pressures managed medically and the remaining

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17 women had an augmentation cystoplasty concomitantly performed. After autologous pubovaginal sling, 91 % of patients were either cured (no pads) or improved (only one pad per day). There were five complications in total with one sling erosion, one vesicovaginal fistula, and one urethral stenosis that all required surgical treatment. Two patients developed detrusor overactivity post procedure that was managed medically. In contrast, Pannek et al. reviewed nine women with SCI who had a transobutator synthetic sling for stress incontinence [30]. Only three were improved (defined as pads reduced by half) or cured, one had urethral erosion and six were failures who required urinary diversion or artificial sphincter to adequately treat their incontinence. The authors do not recommend this treatment given its risk of erosion in those who perform CIC and its lack of efficacy. In the event of intractable incontinence where the urethra is unsalvageable due to urethral erosion or other destructive processes other options include bladder neck closure, augmentation cystoplasty with catheterizable stoma or urinary diversion with simple cystectomy. Colli et al. published their series of 35 patients (69 % female) who had the urethral closed abdominally with a simultaneous suprapubic catheter placement [31]. The authors describe opening the bladder to fully expose the bladder neck, transecting the urethra and closing it with figure of eight sutures. The bladder is mobilized cephalad to create distance between it and the urethral stump. Immediate post-operative complications include one patient who suffered excessive hemorrhage (2000 cc), three wound infections and three urinary fistulas. Later complications included cystolithopaxy in one patient, reoperative replacement of lost suprapubic tubes in three and cystectomy in a patient with suprapubic pain and incontinence via her tract. The advantages of this approach are the preservation of the vesicouretereric junction and no need for bowel harvest. Unfortunately this approach required permanent indwelling catheter with its inherent long term risk of infection and malignancy. Long-term outcomes were published on 34 patients who underwent augmentation cystoplasty with an ileocecal segment and a catheterizable limb of tapered ileum (modified Indiana augmentation cystoplasty) with concomitant urethral anti-incontinence procedure in six [32]. Sixty seven % suffered a complication with the most common being recurrent UTIs and stoma stenosis. Overall, all patients were continent at their latest follow up and there were no new cases of diarrhea which can be associated with ileocecal valve resection. The most recalcitrant cases of incontinence or bladder dysfunction are treated with urinary diversion. In another series, outcomes are presented for 23 patients who underwent ileal conduit diversion with a concomitant simple cystectomy [33]. Simple cystectomy is performed to prevent pyocystis which is all too common in a defunctionalized bladder. Many

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surgeons leave the bladder in situ due to concerns about increased operative time, complications or bleeding. These complications are typically associated with radical cystectomy and few surgeons perform a simple cystectomy where only the bladder body is resected leaving the trigone in place. The authors included a further modification where the bladder is bivalved with a Ligasure® to speed the procedure, ensure hemostasis and prevent blood loss. This modification does not require division of the lateral pedicles of the bladder making this procedure fast (27.5 minutes in this series) and relatively free of hemorrhage (46.7 ml). In one of the few long term analysis of augmentation cystoplasty, Gurung et al. presented the results of this intervention on 19 patients with SCI followed at least 10 years [34]. At 10 years, 15/17 were continent compared to 0 before surgery and maximum cystometric capacity increased from 229 to 494 ml. No patients developed hydronephrosis or renal dysfunction. Four patients developed bladder stones over the ten year period and none developed malignancy. Above all, while there are several surgical options for management of the NGB after SCI, the decision should be based on patient expectations, safety and surgeon expertise. Basic Science of Neurogenic Bladder in SCI A significant amount of research is being done on how the NGB in SCI differs from a normal bladder. At the cellular level, there are changes in the distribution and subtypes of interstitial cells in rat models following SCI [35]. The expression of different interstitial cell populations are associated with reduced innervation, smooth muscle hypertrophy and increased compliance. The bladder urothelium also plays a significant role in afferent bladder signaling [36]. Normal bladder sensation is mediated via purinergic P2X3 and P2X2/3 receptors located in bladder afferent C-fibers. These P2X receptors are selectively activated by ATP. In neurogenic bladder overactivity rat models, there is increased ATP release from the urothelium as compared to normal rats. Purinergic receptors are believed to be a method to regulate bladder hyperactivity. Using IV injection of a P2X3/P2X2/3 antagonist (AF-353), researchers found that by blocking the receptor, there was decreased frequency of non-voiding contractions in rats with neurogenic bladder hyperactivity [37]. The potential role of purinergic receptors as therapeutic targets is being actively pursued [38]. Another selectively activated pathway after SCI pertains to nitric oxide (NO) and NO synthase (NOS). Neuronal NOS (nNOS) is upregulated after SCI and postulated to play a role in neurogenic detrusor overactivity [39]. The expression of nNOS-immunoreactivity in SCI (T10) rats was evaluated and CMG monitoring was performed in vivo with and without intrathecal injection of a nNOS inhibitor. In these studies, the SCI state lead to an increased expression of nNOS in the

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Table 1 Summary of recommended urological testing and monitoring after spinal cord injury Test

Recommendation

Renal ultrasound Annual screening renal ultrasound should be performed for nephrolithiasis and hydroureteronephrosis. [9••] Renal scan Renal scans should be preserved for patients with abnormal ultrasound or deteriorating renal function. [9••] Urodynamic Clinicians should perform post-void residual evaluation assessment (either as part of complete urodynamic study or separately), a complex CMG, pressure flow analysis and EMG during the initial urological evaluation of patients with relevant neurological conditions and as part of ongoing follow-up when appropriate. Clinicians may perform fluoroscopy when available. [3••] Cystoscopy Standard indications for cystoscopy in the evaluation of gross and microscopic hematuria should be followed. [9••, 45] Urine culture Healthy, asymptomatic patients with SCI who present for annual evaluations should not undergo routine urine culture if urinalysis is normal. [9••, 20] BUN/Cr

Serum creatinine is not sensitive for detecting early renal function deterioration in patients with SCI. If clinically suspicious of renal function decline, 24hour urine collection and proper analysis should be performed. [8, 9••]

no stimulation (control) was performed in a canine SCI model [44]. Implanted leads on the pudendal nerve were activated (5Hz) 1 day after SCI. Urodynamic evaluation at 1 and 3 months showed compliance was significantly increased (p<0.05) by pudendal nerve stimulation as compared to control. Additionally, histologic evaluation at 3 months after SCI showed the pudendal nerve stimulated bladders had significantly increased elastic fibers and decreased collagen fibers as compared to control. These results indicate a potential role of pudendal nerve stimulation to delay the progress of bladder fibrosis which frequently occurs in patients with NGB secondary to SCI.

Conclusions Active research continues to advance and improve the urologic care of SCI patients. While standard guidelines are lacking, current literature suggests that clinicians should obtain an annual screening renal ultrasound, perform urodynamics during initial urological evaluation at minimum, and recognize that SCI patients likely have a higher rate of CKD than previously believed (Table 1). In addition, new medications and therapies continue to widen the options available to patients with SCI. Compliance with Ethics Guideline

ventral horn L6-S1 nerves and the addition of NOS inhibitors increased maximum bladder capacity. Researchers postulate that upregulation of nNOS after SCI may enable the emergence of a spinal micturition reflex following SCI. Work continues to expand the medical therapies available to treat neurogenic related detrusor overactivity, beyond anticholinergics [40]. β3-adrenergic receptors are highly expressed in the detrusor and urothelium and are bound by noradrenaline during bladder filling to promote bladder relaxation and facilitate storage. Using in vitro and in vivo SCI models, research has shown that β3-adrenergic receptor agonists directly inhibit afferent nerve firing [41, 42]. This is promising, especially in light of the FDA approval of Mirabegron for treatment of overactive bladder, but there have not yet been any clinical trials using β3-adrenergic receptor agonists in SCI patients. Functional nerve studies are also an active area of research. Yoo triggered bladder contractions via electrical stimulation of the pudendal nerve in seven patients with chronic SCI [43]. The electrical stimulation was delivered to the proximal or distal urethral segments with an intraurethral catheter. This mechanism to trigger bladder contractions supports the presence of a spinal mechanism which generates reflex bladder contractions. This is a potential pathway that can be utilized to restore voiding function after SCI. In other pudendal nerve research, a comparison of pudendal nerve stimulation versus

Conflict of Interest S. Lenherr: none; A. Cameron: received grant from Medtronic. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

References Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1. Cameron AP, Wallner LP, Forchheimer MB, et al. Medical and psychosocial complications associated with method of bladder management after traumatic spinal cord injury. Arch Phys Med Rehabil. 2011;92(3):449–56. 2. Thietje R, Giese R, Pouw M, et al. How does knowledge about spinal cord injury-related complications develop in subjects with spinal cord injury? A descriptive analysis in 214 patients. Spinal Cord. 2011;49(1):43–8. 3. •• Winters JC, Dmochowski RR, Goldman HB, et al. Urodynamic studies in adults: AUA/SUFU guideline. J Urol. 2012;188(6 Suppl):2464–72. These guidelines should be read by anyone involved in the care of patients with lower urinary tract symptoms, including those with neurogenic bladder. While there is a paucity of well

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296 PDE5 inhibitors in modulating detrusor function in overactive bladders: ICI-RS 2011. Neurourol Urodyn. 2012;31(3):300–8. 41. McCarthy CJ, Zabbarova IV, Brumovsky PR, et al. Spontaneous contractions evoke afferent nerve firing in mouse bladders with detrusor overactivity. J Urol. 2009;181(3):1459–66. 42. Kanai A, Wyndaele JJ, Andersson KE, et al. Researching bladder afferents-determining the effects of beta(3) -adrenergic receptor agonists and botulinum toxin type-A. Neurourol Urodyn. 2011;30(5):684–91.

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