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Supplements The Clinical, Social, and Economic Implications of Neurogenic Bladder in Managed Care: Optimizing Pa

Optimizing Therapy and Management of Neurogenic Bladder

David Ginsberg, MD
The 2 primary trials that ultimately led to the approval of BoNT/A for the treatment of NGB studied 691 patients with either SCI or MS. The studies enrolled 275 and 416 patients, respectively, with UI due to NDO (>14 episodes per week) who received 30 intradetrusor injections of BoNT/A 200 U, 300 U, or placebo. The primary end point was the change in baseline in UI episodes per week at week 6. Secondary end points included urodynamic end points (maximum cystometric capacity, maximum detrusor pressure during first involuntary detrusor contraction) and QoL using the Incontinence Quality of Life questionnaire (I-QoL) score. The studies found that both BoNT/A doses significantly reduced UI and improved urodynamic outcomes and QoL in the patients studied. Both doses of BoNT/A were well tolerated with no clinically relevant differences in effect or duration between the 2 doses tested. The most common adverse events were urinary tract infections and urinary retention.14,15 Increased risk of urinary retention and elevated postvoid residual (PVR) were seen in patients who did not perform IC at baseline. Although many initial studies evaluated the higher dosage of 300 U of BoNT/A, these clinical trials trial demonstrated that the 200-U and 300-U doses had similar efficacy, with patients on the 300-U dose experiencing a greater risk of certain adverse events. Thus, the 200-U dose was approved by the FDA due to similar efficacy and an improved risk-benefit ratio compared with the 300-U dose.14-16 The average duration of effect of BoNT/A in patients studied was approximately 9 months.15 Another retrospective trial of 200 patients with NGB receiving BoNT/A found a greater than 50% increase in mean bladder volume to first reflex detrusor contraction and maximum cystometric capacity accompanied by a proportional decrease in maximum detrusor pressure. The benefits of BoNT/A administration persisted over more than 6 months and could potentially prove most cost-effective over this duration of therapy (ie, continuous use of BoNT/A for 5.1 months of therapy or more).1,30 Studies assessing HRQoL following BoNT/A administration in patients with NDO have also been performed, and results in general have demonstrated improvements in QOL as assessed by I-QOL scores or Urinary Dress Inventory (UDI-6) assessment.31,32

Other Pharmacologic Interventions for Neurogenic Bladder and Neurogenic Detrusor Overactivity

Other pharmacologic interventions that have been assessed or are currently undergoing investigation as potential therapies for use in NGB/NDO include several different classes of therapy1:
  • Tricyclic antidepressants (imipramine, amitriptyline)
  • C holinergic agonists (urecholine)
  • Alpha-2 adrenergic agonists (clonidine, tizanidine)
  • Alpha-1 adrenergic agonists (dibenzyline, terazosin, tamsulosin, alfuzosin, doxazosin)
  • Benzodiazepines (diazepam)
  • G ABA-B agonists (baclofen)
  • Opioids (nociceptin)
  • Vanilloids (capsaicin, resiniferatoxin)
  • Nerve growth factor
  • Nitrous oxide agents
Each class of agents exhibits unique mechanisms of action. Many of these agents are experimental, and not all are strongly recommended as potential treatments for patients with NGB/NDO.1 In addition to these drugs, beta-adrenergic agonists have found to be potent relaxant agents of the human detrusor muscle in vitro.33 This class of agents has been studied and found to be effective adjuncts in the treatment of OAB and may have a potential role in the treatment of detrusor overactivity in patients with NGB.34

Surgical Interventions for Neurogenic Bladder and Neurogenic Detrusor Overactivity

Surgical interventions are usually reserved for cases in which nonpharmacologic and pharmacologic interventions fail to control NDO in patients with neurologic disorders. Options include neuromodulation and other surgical interventions.1

Neuromodulation

Sacral neuromodulation (SNM) involves unilateral or bilateral sacral nerve root stimulation. SNM has been used to treat OAB and has been approved by the FDA for treatment of urge incontinence, urinary urgency and frequency, and nonobstructive urinary retention. SNM has been investigated for the treatment of NGB; however, it is not FDA approved for this indication. The exact mechanism of action of SNM is not fully understood; however, SNM uses electrical stimulation to modulate signaling from somatic and afferent nerves involved in the micturition reflex pathway. Original trials excluded patients with NGB because it was initially believed that intact spinal pathways were required for neuromodulation to occur. However, since FDA approval for use in OAB, clinical trials have been under way studying the use of SNM in neurogenic voiding dysfunction. This therapy is considered (though not yet approved by the FDA) in patients with NGB/NDO who have used conservative therapies including lifestyle changes and bladder training plus antimuscarinic therapy but have not achieved adequate relief from symptoms. A 2-stage procedure is performed. Patients initially undergo a 1- to 2-week trial of SNM to assess likelihood of clinical improvement in lower urinary tract symptoms. In this trial, the nerve located at S3 is stimulated by a lead positioned in the sacral foramen connected to an external stimulator that applies the appropriate electric current. Patients are instructed to keep a voiding diary to record both bladder function and urinary symptoms. If the patient reports more than a 50% improvement in symptoms, the patient moves on to stage 2, in which an implantable pulse generator is placed internally via an incision in the upper lateral buttock and development of a subcutaneuous space to house the pulse generator.1,35 A recent meta-analysis found a pooled success rate of 68% for the test phase and 92% for permanent SNM (after a successful test stimulation) in NGB with a 0% complication rate for the test phase and a 24% complication rate for permanent SNM.1,36 Disagreements about the actual applicability of SNM exist. One study evaluating patients with NGB dysfunction due to a variety of neurologic diseases found SNM became ineffective for all patients studied except 1 after a period of 54 months, suggesting a lack of long-term efficacy in this patient population.37 Another more recent trial evaluating use of neuromodulation in patients with NGB dysfunction, both with and without underlying neurologic conditions, demonstrated that greater than 50% of patients in both groups reported moderate or marked improvement in bladder symptoms with SNM over the course of the 2-year assessment period.38 Further study is ongoing in this particular therapeutic area.

Other Surgical Interventions

The most effective surgical method to optimize bladder capacity is enterocystoplasty. This involves the harvesting of a piece of bowel that is configured into a patch, which is placed on a bivalved bladder. Patients undergoing bladder augmentation would be expected to have an appropriate increase in bladder capacity and decrease in bladder storage pressures. Risks of these procedures include bladder stone, UTI, bladder perforation, change in bowel habits, and cancer. For patients who are interested in lower urinary tract reconstruction but are unable or unwilling to perform IC per their native urethra, a continent urinary stoma can be constructed to the skin.1,39

Bladder sphincterotomy may be performed to improve bladder emptying and is primarily performed in patients with detrusor external sphincter dyssynergia who reflex-void to a condom catheter. Indications may include elevated PVR, elevated detrusor pressures, autonomic dysreflexia, and recurrent UTI. Other options for this problem include the use of urethral stents and “pharmacologic sphincterotomy” with the use of BoNT/A.1

In addition, there are surgical options for patients with UI due to an incompetent urinary sphincter. Implantation of an artificial urinary sphincter device is considered the gold standard for treating UI due to sphincteric incontinence in men.1 Female patients with stress UI as a result of a bad outlet would benefit from sling placement. The majority of non-neurogenic women undergoing sling placement for stress UI will have a minimally invasive Prolene mesh sling placed. For neurogenic stress UI, the goal is often obstruction (and regular IC); therefore, a synthetic sling would not be recommended and autologous tissue, either from the rectus fascia or fascia lata, should be used.1,40

Future developments for managing NGB under investigation include lumbar to sacral nerve rerouting, and spinal cord regeneration using genetically modified fibroblasts or neuronal and glial precursors into the spinal cord.1

Conclusion

NGB and its associated lower urinary tract dysfunction present difficult symptoms for patients with neurologic disorders and present clinicians with multiple options and challenges in providing appropriate individualized therapy to improve urinary function and HRQoL. Clinicians managing these patients must choose individualized and optimal treatment pathways among an array of standard, new, and emerging treatments. Better understanding of classes of medical therapies and surgical interventions, both available and emerging, will help clinicians managing patients with neurologic disorders and NGB/NDO to enhance both outcomes and QoL in these patients.

Author affiliations: Department of Urology, Keck School of Medicine, University of Southern California, Los Angeles, CA; Department of Urology, Rancho Los Amigos National Rehabilitation Center, Downey, CA.
Funding source: This activity is supported by an educational grant from Allergan, Inc.
Author disclosure: Dr Ginsberg reports receipt of honoraria and serving as a consultant/advisory board member for Allergan, Inc, American Medical Systems, and Pfizer. Dr Ginsberg also reports receipt of lecture fees for speaking at the invitation of a commercial sponsor from Allergan, Inc.
Authorship information: Concept and design; analysis and interpretation of data; drafting of the manuscript; and critical revision of the manuscript for important intellectual content.
Address correspondence to: David Ginsberg, MD, 1441 Eastlake Ave, Suite 7416, Los Angeles, CA 90033. E-mail: Ginsberg@med.usc.edu.


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