Improving Outcomes in Patients With Refractory Idiopathic and Neurogenic Detrusor Overactivity: Management Strategies

Archives of Physical Medicine and Rehabilitation journal homepage: www.archives-pmr.org Archives of Physical Medicine and Rehabilitation 2015;96(9 Suppl 4):S341-57

JOURNAL-BASED CME ARTICLE

Improving Outcomes in Patients With Refractory Idiopathic and Neurogenic Detrusor Overactivity: Management Strategies David A. Ginsberg, MD,a,b Lynne Kolton Schneider, PhD,c Thomas K. Watanabe, MDd,e From the aDepartment of Urology, University of Southern California, Los Angeles, CA; bRancho Los Amigos National Rehabilitation Center, Downey, CA; cBoca Raton, FL; dDepartment of Physical Medicine and Rehabilitation, Temple University School of Medicine, Philadelphia, PA; and eDrucker Brain Injury Center, Moss Rehab at Elkins Park, Elkins Park, PA.

Continuing Medical Education Information Improving Outcomes in Patients With Refractory Idiopathic and Neurogenic Detrusor Overactivity: Management Strategies Release Date: August 31, 2015 Last Reviewed: February 12, 2015 Expiration Date: August 31, 2016 Time to Complete Activity: 1.0 hour This activity is provided by Global Education Group. Paradigm Medical Communications, LLC is the educational partner.

specializing in medical rehabilitation, musculoskeletal medicine, neuromuscular rehabilitation and central nervous system rehabilitation, urologists, neurologists, primary care physicians, and other interested healthcare practitioners. Learning Objectives Upon proper completion of this activity, participants should be better able to:

  

Faculty David A. Ginsberg, MD Associate Professor of Urology Department of Urology University of Southern California Los Angeles, CA Chief of Urology Rancho Los Amigos National Rehabilitation Center Downey, CA Lynne Kolton Schneider, PhD Boca Raton, FL Thomas K. Watanabe, MD Associate Professor (Adjunct) Department of Physical Medicine and Rehabilitation Temple University School of Medicine Philadelphia, PA Clinical Director, Drucker Brain Injury Center Moss Rehab at Elkins Park Elkins Park, PA Target Audience This activity has been designed to address the educational needs of physicians, physician assistants, and nurse practitioners in the field of physical medicine and rehabilitation, including those

Identify a systematic approach to the evaluation and diagnosis of overactive bladder and neurogenic detrusor overactivity (NDO). Discuss individualized management plans for NDO that incorporate evidence on treatment efficacy, benefits, and drawbacks, as well as patient perspectives and potential need for timely referral. Describe a multidisciplinary team approach to care of patients with NDO that includes communication strategies for incorporating patient perspectives and establishing realistic patient expectations.

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0003-9993/15/$36 - see front matter ª 2015 by the American Congress of Rehabilitation Medicine http://dx.doi.org/10.1016/j.apmr.2015.05.016

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Name of Faculty or Presenter Reported Financial Relationship David A. Ginsberg, MD

Consultant: Allergan, Inc Research Support: Allergan, Inc; Medtronic, Inc Honoraria: Allergan, Inc Lynne Kolton Schneider, PhD No financial relationships to disclose Thomas K. Watanabe, MD No financial relationships to disclose

The planners and managers reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME activity:

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Neurogenic detrusor overactivity

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Abstract Neurogenic detrusor overactivity (NDO) is a lower urinary tract dysfunction commonly seen in rehabilitation settings. The emotional, medical, and financial consequences of NDO can be substantial and management typically requires a multidisciplinary team approach. Physiatrists need to be able to identify patients who require referral to specialists for diagnostic testing or higher-tiered treatment and need to engender open lines of communication between their patients and all treating clinicians. This requires an understanding of the evaluation, diagnosis, and treatment of neurogenic lower urinary tract dysfunctions. Archives of Physical Medicine and Rehabilitation 2015;96(9 Suppl 4):S341-57 ª 2015 by the American Congress of Rehabilitation Medicine

Neurogenic detrusor overactivity (NDO) and refractory idiopathic overactive bladder (OAB) are lower urinary tract dysfunctions commonly seen in rehabilitation settings. Common populations affected by these disorders include patients with multiple sclerosis (MS), spinal cord injury (SCI), Parkinson disease, stroke, dementia, and diabetes. Both NDO and OAB involve a disturbance in storage and emptying of the bladder. NDO is a urodynamic condition defined as uninhibited, involuntary bladder contraction during the filling phase of a urodynamic study.1 Neurogenic bladder involves abnormal bladder function and sphincter dysfunction secondary to central nervous system injury or neurologic disease.2,3 According to the Standardization Subcommittee of the International Continence Society, OAB is defined as a symptom syndrome suggestive of lower urinary tract dysfunction, characterized by urinary urgency, with or without urge urinary incontinence (UI), and usually with urinary frequency and nocturia.1,3,4 The medical, psychosocial, and economic consequences of NDO and OAB are significant, including increased morbidity and mortality. NDO can be detrimental to the upper urinary tract, causing hydronephrosis or renal failure,5,6 and the lower tract, resulting in urinary tract infections7,8 or kidney or bladder stones.8 Historically, renal failure was the leading cause of death in patients with SCI. However, earlier diagnosis and advances in treatment of neurogenic lower urinary tract dysfunction (NLUTD) have reduced the incidence of renal failure in patients with SCI, with respiratory infections now being the leading cause of death.9 NLUTD is rarely a significant cause of mortality in patients with MS or Parkinson disease, but it remains a risk among patients with meningomyelocele who do not undergo urologic treatment.9 Chronic incontinence can lead to dermatologic problems and skin breakdown.10,11 In addition, studies have shown that poststroke UI is negatively associated with 2year survival rates, worsened disability as measured by the Barthel Index, and increased rates of institutionalization.12 In fact, UI is a powerful predictor for whether patients with stroke can be discharged to home from an inpatient setting.13 UI has

Presented to the American Academy of Physical Medicine and Rehabilitation, November 13e 16, 2014, San Diego, CA. Supported by an educational grant from Allergan, Inc. Independent medical writing assistance was provided by Paradigm Medical Communications, funded by the unrestricted financial grant from Allergan, Inc. Authors had full access to all of the data in this article and take complete responsibility for the integrity and the accuracy of the article. Allergan, Inc. did not impose any impediment, directly or indirectly, on the publication of the article. Disclosures: Ginsberg is a consultant for, and has received grant/research funds and honoraria from, Allergan, Inc. He has also received grant/research funds from Medtronic. The other authors have nothing to disclose.

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also been associated with an increased risk of falls and fractures in older adults14 and in persons in nursing homes,15 leading to higher rates of institutionalization among frail older persons.16 The impact of NDO or OAB on health-related quality of life is significant,17-20 and NDO with UI causes a significantly greater effect on health-related quality of life than NDO without incontinence.19 UI and OAB are associated with depression,21 loss of self-respect or dignity, decreased productivity in the workplace, interference with sleep22 and sexual activity,23 and a restriction of social activities because of fear of UI or because of the need for frequent voids.24 In addition, incontinence pads are particularly expensive, and their use has been estimated to account for nearly two thirds of the annual per patient costs of OAB management.25 In fact, in 2009, the cost to treat OAB was estimated at nearly $25 billion,26 and the overall cost of nonneurogenic OAB with urge incontinence was $65.9 billion in 2007 and is estimated to reach $76.2 billion by 2015.27 Other cost factors include diagnostic testing, medications, health care providers, equipment, and costs associated with lost productivity and health-related consequences.28-30

Etiology and symptoms The function of the lower urinary tract is primarily to store and void urine. The lower urinary tract is regulated by a neural control system located in the brain and spinal cord that coordinates the activity of the bladder and bladder outlet/urinary sphincter (fig 1).9 Consequently, NLUTD results from any disturbance in the nervous systems that control the lower urinary tract. Disruption of the connection between the pontine micturition center and the sacral cord (ie, suprasacral lesion/injury) results in poor coordination between the detrusor muscles and the external urethral sphincter muscles, leading to detrusor-sphincter dyssynergia. Poor sphincter competence or sphincter incompetence can lead to stress UI. Detrusor overactivity is associated with suprasacral neurologic lesions and is characterized by involuntary detrusor contractions during the filling phase that may be spontaneous or provoked and can result in increased urinary frequency, urgency, and urge incontinence (or UI). The 2 most common causes of NDO are MS and SCI; other common causes include Parkinson disease and stroke.20 As seen in appendix 1, a wide range of neurologic conditions have been associated with NDO.31 Supraspinal neurologic diseases (eg, Parkinson disease, cerebral palsy) occur above the pontine micturition center and generally cause NDO with synergistic voiding (eg, no detrusor-sphincter dyssynergia). Suprasacral injuries involving the spinal cord result in NDO with detrusor-sphincter dyssynergia and an increased risk for other urologic

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Fig 1

Neural control of micturition. Photo credit: Blarb/Shutterstock.com.

complications (eg, hydronephrosis, vesicourethral reflux, urolithiasis).32 Sacral spinal cord lesions, associated with spina bifida or myelodysplasia, and peripheral neurologic disease are associated with acontractile detrusor, with reduced perianal sensation and sphincter tone. However, the high rate of exceptions to these categorizations necessitates proper and comprehensive neurourologic evaluations. Patients with NDO often present with UI; however, the symptoms vary.33 An estimated 23.6% of patients with stroke, one third of patients with Parkinson disease, half of patients with MS, and 52.3% of patients with SCI have UI.34 The incidence of bladder dysfunction, including but not solely caused by NDO, is also high,

List of abbreviations: MS NDO NLUTD OAB PTNS SCI SNM UI

multiple sclerosis neurogenic detrusor overactivity neurogenic lower urinary tract dysfunction overactive bladder percutaneous tibial nerve stimulation spinal cord injury sacral neuromodulation urinary incontinence

affecting 68% of those with SCI, 37% to 72% of patients with MS, and 35% to 70% of patients with Parkinson disease.35 The interplay between the urodynamic condition and symptom awareness/presentation can be complex and hard to predict. Patients with MS often manifest with frequency, urgency, and urge incontinence. They typically have intact sensation; as such, they are aware of the urge feelings. However, they may also have problems with holding/ storing urine or incomplete emptying. Patients who have had a stroke may also have frequency, urgency, and urge incontinence. Their sensation is also usually intact; however, sometimes they may not feel uninhibited bladder contractions and may have UI without their knowledge. The bladder consequences of SCI depend on the degree of the spinal injury. Patients with complete SCI usually will have UI without any bladder sensation; however, they may be aware of bladder activity because of autonomic dysreflexia. In contrast, patients with incomplete SCI may have some sensation. Finally, management of patients with Parkinson disease can be particularly challenging because they can have UI, urgency, and incomplete emptying combined with the inability to move rapidly enough to get to the toilet. There are also nonurologic causes for UI. For example, some patients may not be able to communicate their need to urinatedwhether owing to aphasia, dysfluency, dysphonia, or

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Neurogenic detrusor overactivity even language barriers. They may have impaired or decreased mobility, poor dexterity, or confusion and delirium. Older patients can have nonneurologic and neurologic urinary issues (eg, normativepressure hydrocephalus).36 Women might have concomitant stress UI, prolapse, or OAB; men may also have prostate problems such as benign prostatic hyperplasia.

Evaluating refractory idiopathic OAB and NDO patients Urinary symptoms in neurologic patients may stem from nonneurologic etiologies, such as bladder abnormalities, including bladder cancer, bladder stones, or interstitial cystitis; prostate or urethral abnormalities, prostate cancer, or urethral stone (in men); pelvic prolapse (in women); or stress UI.37 Symptoms can also stem from urogenital infections (eg, bacterial cystitis, prostatitis, urethritis). In contrast with uncomplicated OAB, which is a clinical syndrome primarily diagnosed through urologic history, urogenital physical examination, and urinalysis, diagnosis of NDO is generally more involved. However, some patients with OAB may require a more extensive evaluation such as that recommended for NDO. The evaluation for patients with suspected NDO involves an expanded physical examination (pelvic, rectal, neurologic), urinalysis and urine culture, blood chemistry, and a more comprehensive history that should encompass medical, social, and general history; history of diabetes, stroke, accidents, or surgeries, especially those involving the spine or central nervous system; quality of life; and social history, including smoking and drug or alcohol use and hereditary or familial risk factors. Physical examination needs to note sensations from S2-5 on both sides, including presence of sensation, type of sensation, and reflexes; anal sphincter tone; and prostate examination (men) or evaluation of pelvic organ prolapse (women). The urologic history should include information about initiation of micturition, including normative, precipitate, reflex, strain, and Crede´; whether the patient is catheterized; bladder sensations; relief after voiding; and incontinence patterns. A bowel and sexual history may also be important.9 Neurologic history should address acquired or congenital neurologic conditions (eg, parkinsonism, MS, stroke), mental status, and onset and evolution of any neurologic symptoms; and spasticity, mobility, hand function, and presence of autonomic dysreflexia.9 Helpful studies include a bladder or renal ultrasound if indicated and urodynamics, including postvoid residual volume.38-40 The key for evaluating the patient with presumed NDO is multichannel urodynamic testing.9,41 Additional assessments that may be used to supplement the findings include questionnaires, diaries, and pad tests.42 The clinical presentation, symptoms, and course of NDO all depend on the location and extent of the underlying neurologic condition.43 Not all patients will require a urodynamic workup. Some patients, including those with MS, may be treated empirically; a full discussion of this is beyond the scope of this article. Many patients with MS, especially women, can be empirically treated without a concern of upper tract damage. However, if there is any concern or suboptimal response to therapy, then further evaluation with urodynamics would be indicated. However, symptoms and the physical examination do not always correlate with the injury type, extent, or level or with the prognosis or danger to kidney function.44 Patients with SCI or adult spina bifida www.archives-pmr.org

S345 require an urodynamic evaluation to ensure safe bladder storage pressure prior to determining treatment.

Pharmacologic and nonpharmacologic treatment options for NDO Currently, the only guidelines that specifically and solely address NLUTD are by the European Association of Urology in 2011.9 In order of importance, the European Association of Urology guidelines report the goals of treatment for NDO are to (1) protect the upper urinary tract by reducing the risk of NLUTD, (2) improve the level of urinary continence, (3) preserve and restore lower urinary tract function, and (4) improve patient quality of life by relieving symptoms.9 Appendix 2 lists the range of available guidelines related to diagnosis and management of bladder problems in adults.9,33,45-47 Not all treatments recommended for OAB are equally effective or beneficial for patients with NDO. There are numerous objective and subjective approaches that can be used for assessing patient baseline parameters and defining treatment success. Bladder diaries are useful tools to evaluate baseline lower urinary tract dysfunction, follow changes with treatment, and help monitor patient satisfaction; however, patients do not always maintain diaries optimally. Other potential outcomes that should be factored include the number of urinary tract infections. For patients with an OAB, success is determined by patient satisfaction, which can objectively be evaluated by a variety of validated questionnaires. For patients with NDO, success is often a combination of clinical and urodynamic outcomes. Weighing pads before and after exercise is a more objective approach for determining whether a patient is incontinent and, if so, how much a patient is leaking. Similarly, medications (eg, pyridium) can determine if there is UI. Evaluating the number of urinary tract infections and episodes of autonomic dysreflexia in patients with SCI can also be used to define success. Qualitative outcomes (eg, community participation, self-esteem, sleep quality and quantity, mood, other measures of quality of life) are also important. Urodynamics allow for an objective measurement of improvement and are an extremely important measure for patients that have elevated bladder pressures that place their upper tracts at risk before initiation of therapy.

First-line treatments According to the European Association of Urology guidelines for NLUTD, first-line options include a range of noninvasive conservative treatments (eg, behavioral modification techniques, lifestyle modifications, prompted voiding, timed voiding/bladder training). Pelvic floor muscle exercises aimed at improving continence may be helpful in select patients, and biofeedback may be useful in supporting voiding pattern modification.9 These recommendations are similar to those of the American Urological Association/Society for Urodynamics, Female Pelvic Medicine & Urogenital Reconstruction guidelines for OAB, in which the first line of treatment involves lifestyle changes and behavioral modifications, with or without antimuscarinics.46 Consistent with both the European Association of Urology and American Urological Association/Society for Urodynamics, Female Pelvic Medicine & Urogenital Reconstruction guidelines, first-, second-, and third-line treatments are tiered in order of invasiveness, and per the guidelines, they are recommended to be used in a stepwise approach.

S346 Lifestyle changes and behavioral modifications can include modifying fluid and caffeine intake, timed voiding, pelvic floor muscle training, biofeedback, and/or toileting assistance.9,33,48-50 Nicotine irritates the detrusor muscle and causes bladder contractions and urgency, and repeated coughing can cause urinary leakage; consequently, clinicians recommend that patients with OAB or NDO quit smoking. Straining associated with constipation can also put pressure on the bladder; as such, interventions to minimize constipation are warranted. Bladder rehabilitation techniques, generally based on electric or magnetic stimulation, aim to help patients with NLUTD regain voluntary control over their lower urinary tract. Some of the techniques (electrostimulation, intravesical electrostimulation, peripheral temporary electrostimulation) may be beneficial to a small group of patients (eg, those with MS or an incomplete SCI); however, there is a lack of well-designed studies to evaluate the benefits and appropriate candidates for these techniques.9 Some patients may prefer a nonpharmacologic, behavioral approach. In general, some patients do respond well to these firstline approaches; however, lifestyle modifications are often labor intensive and time consuming, requiring active patient participation and persistence, and the results are very gradual.51-53 Behavioral training is most valuable in patients who have some degree of bladder control and intact bladder sensation, including those with neurologic lesions involving the brain (eg, cerebrovascular disease, Parkinson disease, multiple system atrophy, dementia, cerebral palsy) and those with MS, incomplete SCI, transverse myelitis, and diabetes mellitus.54

Second-line options Pharmacologic approaches comprise second-line therapy for both NDO and OAB and include antimuscarinics and the beta3-agonist mirabegron. As yet, there is no single optimal medical therapy for NLUTD, and many patients require combination pharmacotherapy.9 Medication selection depends on patient history of prior antimuscarinic use, prior adverse events, and their impact on the patient, patient preferences, whether there are any comorbid conditions, and the use of other medications. In general, there are 3 classes of agents used to treat OAB: antimuscarinics, the beta3-agonist mirabegron, and tricyclic antidepressants (see supplemental table S1, available online only at http://www.archives-pmr.org/). Antimuscarinic agents are first-line choice for treating NLUTD because of their established action to stabilize and relax the detrusor muscle, leading to improved bladder compliance and reduced lower urinary tract symptoms.9 Among the commonly used antimuscarinics are oxybutynin chloride, tolterodine tartrate, solifenacin, darifenacin, trospium chloride, and fesoterodine. These agents normalize intravesical pressure and increase cystometric bladder capacity.55 They significantly reduce maximum detrusor pressure; however, reduction in detrusor overactivity persists only while the patient remains on the treatment. In addition, antimuscarinics are associated with several commonly noted adverse effects, particularly dry mouth and constipation, which can interfere with patient adherence to treatment. Although there are differences in tolerability and safety between the agents, there is no compelling evidence for differential efficacy across the medications.46 Patients with NDO may benefit from higher doses of medications than patients with OAB (eg, 30mg oxybutynin, 8mg tolterodine extended release, 90mg trospium), which can lead to

D.A. Ginsberg et al increased incidence of adverse effects.9,32,56,57 American Urological Association guidelines for OAB recommend the use of oncedaily, extended-release dosing regimens whenever possible, to limit the bothersome side effects associated with the peaks and troughs of multidosing, immediate-release regimens.46 This approach and alternative routes of administration (transdermally, intravesically) may help reduce side effects in patients with NDO.9 There has been growing awareness that antimuscarinic treatments may have adverse central nervous system effects, including headaches and cognitive impairment.58,59 Studies have shown that there are differences among the various antimuscarinic agents, predominantly in their ability to penetrate the blood-brain barrier.58,60,61 Specifically, oxybutynin and other lipophilic tertiary amines are more likely to cross the blood-brain barrier than are hydrophilic quaternary amines (eg, trospium chloride), which have few reports of adverse central nervous system effects.58 In fact, the potential for anticholinergic central nervous system events has been included in product labeling for oral oxybutynin since 2008. Clinicians need to be cognizant of the potential for cognitive impairment with nonselective antimuscarinic agents, particularly among older patients or those with diseases or injuries affecting the brain, and select treatment on an individualized basis.62,63 Antimuscarinics should not be used in patients with narrowangle glaucoma unless otherwise approved by the treating ophthalmologist; should be used with extreme caution in patients with impaired gastric emptying or a history of urinary retention, except for the patient with NDO where the goal in medical therapy is placing the patient into urinary retention and bladder management with clean intermittent catheterization; and should be used with caution in patients using other medications with anticholinergic properties or in frail patients with OAB/NDO.46 Although longterm persistence with pharmacotherapy is required for consistent results, adherence after 3 months is relatively poor because of bothersome side effects (eg, dry mouth, constipation).64 Clinicians need to manage constipation and dry mouth before abandoning effective antimuscarinic therapy.46 Although antimuscarinic agents do not have a Food and Drug Administration indication for the management of NDO, they are well-accepted as first-line pharmacotherapy. Studies have demonstrated efficacy of at least 4 of them (oxybutynin, trospium chloride, tolterodine, darifenacin) in this patient population.9,32,55,65 The detrusor muscle contains beta-adrenoceptors. Human bladder and urothelium contain beta1-, beta2-, and beta3adrenoceptors66; 97% of beta adrenoceptors in the human bladder are beta3.67 Beta2-adrenoceptors are important in muscle relaxation through activation of adenylate cyclase; evidence indicates that beta3-adrenoceptors mediate relaxation of human detrusor muscle.67-69 Consequently, selective beta3-adrenoceptor agonists have been investigated and developed as treatment for OAB syndrome.66 Evidence suggests the effect of beta-adrenoceptor stimulation is similar in both normative bladders and neurogenic bladders. Mirabegron is the first and only beta3-agonist with Food and Drug Administration approval for OAB. It has minimal intrinsic activity on beta1- or beta2-adrenoceptors and therefore minimizes or eliminates the undesirable adverse effects associated with them (eg, increased heart rate, muscle tremors).70 The incidence of dry mouth associated with mirabegron is similar to that with placebo and is reportedly 3fold lower than that with tolterodine.71,72 The most common side effect is dose-related elevation in blood pressure, which occurs in 7.5% to 11.3% of patients.73 Mirabegron is taken once daily and can

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S347 be beneficial for refractory patients with moderately severe baseline UI and urinary frequency.

Fig 2 Sacral neuromodulation. Reprinted with permission from medicalimages.com.

be used as a primary treatment or add-on therapy with an antimuscarinic in OAB.74,75 Tricyclic antidepressants, including imipramine, doxepin, desipramine, and nortriptyline, are frequently used for pain and sleep in the rehabilitation setting. Although they have an anticholinergic and direct muscle relaxant effect on the urinary bladder, they are not Food and Drug Administration approved for OAB or NDO. In fact, physiatrists and other clinicians need to be aware of their effects on the bladder and the potential for adverse effects.46

Third-line options Patients who have failed to respond to behavioral interventions or pharmacotherapy may be considered for any of the third-line options, including percutaneous tibial nerve stimulation (PTNS), sacral neuromodulation (SNM), or injections with botulinum toxin A. Intravesical pharmacotherapy, including intravesical administration of anticholinergics, may be beneficial in minimizing detrusor overactivity in some patients. Catheterization may be appropriate for a select group of patients with NDO in whom detrusor overactivity can be pharmacologically controlled.9 Percutaneous tibial nerve stimulation PTNS involves stimulation of the posterior tibial nerve. It is the least invasive form of neuromodulation, involving retrograde stimulation of the sacral nerve plexus. This therapy is Food and Drug Administration approved for OAB; however, there is also a fair amount of data on use of PTNS in patients with MS, leading to statistically significant improvements in urodynamic and clinical parameters after 12 weeks.76 Further, chronic PTNS appears effective in patients with MS.77 Other, albeit limited, studies in patients with NDO appear promising.33 An important component of successful PTNS treatment is compliance with the protocol: patients are initially treated in the office once weekly for 12 weeks; patients who demonstrate a response are then treated on a once-monthly basis. Currently, PTNS is only Food and Drug Administration approved for OAB and urge incontinence and may www.archives-pmr.org

Sacral neuromodulation As with PTNS, SNM is approved for the treatment of the symptoms of OAB, including urge incontinence and significant symptoms of urgency-frequency alone or in combination, among patients who have failed or cannot tolerate more conservative treatments. It is also indicated for fecal incontinence and nonobstructive urinary retention in patients who have failed or cannot tolerate more conservative treatments, and it is used off-label for patients with neurogenic bladder/NDO.46,78 SNM involves stimulation of the third sacral foramen, the nerve most responsible for bladder function (fig 2). The treatment is performed in stages. The initial test phase identifies patients who respond to temporary percutaneous nerve evaluation. Patients who respondddefined as those who demonstrate at least a 50% improvement in target symptomsdcan then proceed to full implantation of the pulse generator and leads. The implanted device includes a battery that must be changed every 5 years; the safety of full-body magnetic resonance imaging has not been established for patients with this device and is not recommended by the manufacturer. Although SNM is a well-established and widely accepted treatment for refractory nonneurogenic lower urinary tract dysfunction, its use in patients with NLUTD is unclear.79 Data on its efficacy in neurogenic patients are lacking.9 A prospective multicenter study is currently underway in Switzerland to evaluate the efficacy and value of SNM in patients with NLUTD.79 Among patients with NDO, SNM has been most often studied in the MS population, but it is generally limited to those patients who do not have progressive diseasedspecifically, only patients with relapsing-remitting MS who have not had a relapse in at least the prior 2 years. A recent study examining efficacy of SNM in NDO noted the results depend on the underlying neurologic disease.80 Specifically, 54% of patients with MS, 46% of those with an incomplete SCI, and only 25% of those with Parkinson disease had a positive test stimulation result. After a mean follow-up of 4.3 years for those receiving the treatment, 75.7% of implanted patients considered the treatment successful.80 A retrospective case study of 23 patients in China with neurogenic bladder and bowel dysfunction secondary to spinal cord disease found 13 patients responded to the initial testing phase with SNM, but only 6 responded to permanent SNM.81 However, combining chronic SNM with other treatments improved symptomatic relief.81 Studies on patients with intractable (nonneurogenic) urge incontinence, urgency-frequency, and retention have demonstrated safety and sustained efficacy of the device in those patients who have responded to the initial test phase.82-84 Patients with the device who reported a significant decrease in 24-hour pad weight reported substantially greater satisfaction than patients who did not report improvement in this incontinence parameter.82 Lack of efficacy and device pain are 2 factors that contribute to device dissatisfaction.82 Botulinum neurotoxin injections OnabotulinumtoxinA is the only third-line option that is Food and Drug Administration approved for NDO and for urge incontinence and OAB (see supplemental table S1). It is an effective alternative for patients with NDO who fail pharmacotherapy40,85 and is safe and effective in catheterized refractory NDO patients.9,86-89 The European Association of Urology guidelines note that “botulinum toxin injection in the detrusor is the most effective minimally

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Fig 3 Botulinum toxin injections into the bladder. Reprinted with permission from Elsevier.91

invasive treatment to reduce neurogenic detrusor overactivity.”9(p34) Injections with onabotulinumtoxinA have been shown to significantly improve quality of life.90 The most common adverse effects associated with onabotulinumtoxinA treatment include urinary tract infections, urinary retention (a temporary risk), hematuria, fatigue, and insomnia.89-91 There is a black box warning in the United States, stating that the effects may spread from the area of injection to produce symptoms consistent with botulinum neurotoxin effects, from an hour to a week after the injections.92 In addition, clinicians need to be aware if the patient is undergoing onabotulinumtoxinA treatments for other conditions (eg, spasticity) because there is a total dose limit of 360 units over a 3-month period of time and a similar interval between injections.92 Injections can be performed in the office using either a rigid or flexible cystoscope.91 Typically a patient receives 20 to 30 injections of 0.5 to 1mL (approximately 6e10U) onabotulinumtoxinA in the bladder, located 1cm apart and 2mm into the detrusor (fig 3). A short video of one of the authors performing the procedure is available in supplemental video S1 (available online only at http://www.archives-pmr.org/). The Food and Drug Administration approved doses are 200U for NDO and 100U for OAB. However, for patients with NDO/neurogenic bladder that continue to void volitionallydoften in MS and Parkinson diseasedthe 100-U dose is usually considered to reduce the risk of postinjection retention requiring clean intermittent catheterization.

Fig 4

Most injection templates do not include injections into the trigone. Patients should be observed for at least 30 minutes after the injections. Treatment effects persist for 6 to 10 months89 and are dose dependent. Patients may benefit from a local anesthetic prior to the injections. There are 4 botulinum neurotoxin products available in the United States, but they are not interchangeable; only onabotulinumtoxinA has Food and Drug Administration approval for NDO and OAB and urge incontinence. The other marketed formulations of botulinum neurotoxin are abobotulinumtoxinA, incobotulinumtoxinA, and rimabotulinumtoxinB.93-95 Data from 2 double-blind, placebo-controlled trials demonstrated the safety and efficacy of onabotulinumtoxinA injections for NDO and led to its Food and Drug Administration approval.90-92 The first trial involved 154 patients with MS and 121 with SCI.90 The second trial involved 227 patients with MS and 189 with SCI, all of whom had at least 14 UI episodes per week and had already failed oral therapy.91 The patients were randomized to receive 30 intradetrusor injections of onabotulinumtoxinA 200U (nZ227), onabotulinumtoxinA 300U (nZ223), or placebo (nZ241). For both trials, the primary endpoint was change from baseline at week 6 in UI episodes per week; secondary endpoints included urodynamic outcomes of maximum cystometric capacity, maximum detrusor pressure during the first involuntary detrusor contraction, volume at first involuntary detrusor contraction, quality of life as measured by the Incontinence Quality of Life Questionnaire, and adverse events.90-92,96 In each trial both doses of onabotulinumtoxinA led to significant decreases in UI episodes per week versus placebo for patients with either MS or SCI (fig 4). In the first trial, the reduction in UI episodes per week was 21.8 and 19.4 among patients receiving onabotulinumtoxinA injections, 200 and 300U, respectively, compared with a reduction of 13.2 episodes per week among patients receiving placebo.90 Similarly, the number of UI episodes per week decreased by 21 and 23 among patients in the second trial receiving onabotulinumtoxinA 200 and 300U, respectively, compared with a reduction of 9 UI episodes per week among those receiving placebo.91 Significant differences were also observed in the secondary endpoints in both studies (fig 5).92 At week 6, treatment with onabotulinumtoxinA led to significant improvements in maximum cystometric capacity, significant improvements in maximum detrusor pressure during the first involuntary detrusor contraction, significant improvements in Incontinence Quality of Life Questionnaire compared with placebo, and longer median time to patient request for retreatment (36e42 vs 13wk, respectively). Further, both trials noted a significantly greater

Mean change from baseline in weekly UI episodes in MS and SCI. Reprinted with permission from Springer Healthcare.96

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Fig 5

OnabotulinumtoxinA phase 3 trials in NDO: urodynamics.92

proportion of patients achieving dry status in the active treatment arms versus placebo. There were substantial and significant decreases in bladder pressures associated with the 2 treatment arms compared with placebo.92,96 However, the studies demonstrated no clinically relevant benefit in efficacy or duration for the 300-U dose over the 200-U dose, and there was a greater risk of urinary retention reported with the higher dose, resulting in approval for the 200-U dose.90-92,96 The most frequently reported adverse events noted within the first 12 weeks after intradetrusor injection were urinary tract infection, seen in 24% of patients treated with onabotulinumtoxinA 200U and 17% receiving placebo, and new onset urinary retention requiring catheterization, seen in 17% and 3%, respectively. As such, it is important to discuss the possibility of selfcatheterization with potential patients before beginning these treatments and make sure they are willing and able to initiate catheterization posttreatment, if required, for urinary retention.92 AbobotulinumtoxinA has also been evaluated and shown to be effective; however, it does not have Food and Drug Administration approval for NDO. A trial involving 22 patients with NDO (13 men, 9 women) evaluated successive doses of abobotulinumtoxinA injected repeatedly into the bladder. Twelve patients received 500U, and 10 received 1000U. There was a constant effect after the 4 sets of injections, with similar duration and efficacy for both doses.97

Surgical options: rare cases Surgical options are reserved as a last resort for patients who have not responded to any other approaches. When appropriate, patients may undergo bladder augmentation or urinary diversion; myomectomy and sacral rhizotomy are very rarely performed.9,33

Multidisciplinary care and physician-patient communication Optimal management of patients with NDO requires a multidisciplinary team approach.98-100 Typically the primary care www.archives-pmr.org

physician and the physiatrist are aware of all active medical conditions and must be updated on medication or treatment decisions. In addition to the physiatrist, many patients in rehabilitation settings see a neurologist, nurse/nurse practitioner, and urologist for the evaluation and management of the bladder problems. Additionally, many patients need guidance and support from a wide range of other health care workers, including a nutritionist to monitor not only nutrition but also hydration, a counselor or social worker to provide emotional guidance, and a case manager to coordinate the patient’s other needs (transportation, acquiring durable medical equipment or materials, negotiating insurance, etc). The patient’s caregivers can, and in many cases should, be an integral part of the team. A recent study investigated the follow-up care of patients with NDO at 1 year.2 The study involved 46,271 patients overall: 9315 had SCI and 4168 had MS. Overall, 39% of the patients had been seen by a urologist at 1 year, including 36% of patients with SCI and 26% of patients with MS. More than half of the patients with MS (53%) had been seen by a neurologist compared with 18.5% of patients with SCI. However, <1 in 5 patients with SCI (18%) and only 7.5% of patients with MS had received physiatric care.2 Because of the potential impact of NDO on quality of life and other health-related parameters, it is imperative that physiatrists follow-up and monitor their patients throughout treatment for NDO, including establishing open lines of communication with the other treating clinicians. Facilitating a patient-provider relationship based on trust, open dialogue, and good communication has been shown to be beneficial for a patient’s health-related quality of life.101 This is true for all members of the multidisciplinary team. The importance of establishing appropriate treatment expectations cannot be underestimated. In a survey of 5400 patients, nearly half (45.4%) had discontinued treatment for bladder dysfunction because of unmet treatment expectationsdnot necessarily treatment failureddespite objective treatment success.102 Patients must understand their various treatment options, including possible side effects; they need to understand the treatment goal may not be a cure.

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In summary, both NDO and OAB are common among patients in rehabilitation settings, and both can have significant negative impact on medical stability and quality of life. These patients need to be differentially identified and evaluated by the appropriate clinician(s) and treated accordingly (see case studies in appendices 3 and 4). In certain cases, patients can be treated empirically based on clinical presentation, but in most cases of NDO, urodynamic studies are required. The pathophysiology may not be obvious. Initial treatment approaches focus on noninvasive lifestyle and behavioral modifications; however, many patients with NDO fail to adequately respond to these interventions, requiring second-tier options. Pharmacotherapies, particularly with specific antimuscarinics, have shown some efficacy for NDO. There are several third-tier options to treat patients who have failed oral pharmacologic therapy, including SNM, PTNS,

Appendix 1

and botulinum toxin injections. Only botulinum toxin injections are specifically approved for management of NDO.

Keywords Botulinum toxins, type A; Lower urinary tract symptoms; Rehabilitation; Spinal cord diseases; Urinary bladder; Urinary incontinence

Corresponding author David A. Ginsberg, MD, 1441 Eastlake Ave #7416, Los Angeles, CA 90033. E-mail address: [email protected].

Neurologic conditions associated with NDO Peripheral Nervous System and Neuromuscular Junction

Brain

Spinal Cord

Cerebellar ataxia Cerebral palsy Dementia Multiple system atrophy Neoplasms Parkinson disease Stroke

Acquired immune deficiency syndrome Ankylosing spondylosis and disk disease Guillain-Barre´ syndrome Herpes zoster Lyme disease Multiple sclerosis Myelomeningocele Pernicious anemia Poliomyelitis Spinal cord injury Tabes dorsalis Tethered cord syndrome and short filum terminale Transverse myelitis Tropical spastic paraparesis

Diabetic neuropathy Myasthenia gravis Pelvic plexus injury

31

Reprinted with permission of Haymarket Media.

Appendix 2

Guidelines for OAB and NDO

Year

Organization/Society

Description

2014

Guideline on OAB in adults: Gormley et al46

2011

American Urological Association/Society for Urodynamics, Female Pelvic Medicine & Urogenital Reconstruction European Association of Urology United Spinal Association, Multiple Sclerosis Association of America European Association of Urology

2006

Paralyzed Veterans of America

2013 2012

Guidelines on UI: European Association of Urology45 Consensus statement on improving bladder care in MS/SCI: Ellsworth et al33 Guidelines on neurogenic lower urinary tract dysfunction: Pannek et al9 Clinical practice guidelines for bladder management in SCI: Paralyzed Veterans of America47

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Appendix 3 Case 1 Case 1 is a 44-year-old woman, gravida 3 para 2, with MS diagnosed at age 33 years, who uses a cane when walking; however, she has been relying on a wheelchair with increased frequency. Fatigue and spasticity are contributing to her decreased mobility. She is on baclofen to treat her muscle spasticity, which can cause loss of bladder control in approximately 1% of patients.103

Complaint and evaluation Her presenting complaints are urinary frequency/urgency and worsening UI. She is currently taking solifenacin 5mg without optimal response. Her examination is unremarkable, Urinalysis: white blood count, 6 to 10; postvoid residual volume: 95mL.

Initial treatment The treating clinician considers numerous treatment options: increasing the dose of solifenacin from 5 to 10mg; adding or switching to mirabegron; referring her for pelvic floor muscle training; SNM; performing urodynamics; and botulinum neurotoxin injections. She is not likely to be a good candidate for pelvic floor muscle training and is not willing to try more involved treatments; therefore, the clinician adds mirabegron to the solifenacin.

Follow-up The patient reports minimal benefit to the addition of mirabegron to solifenacin. The clinician now performs urodynamics, which demonstrate detrusor overactivity with significant leakage. The clinician discusses the benefits and risks associated with indwelling (Foley) catheters and suprapubic tubes and notes that these options may be ideal for a group of patients, but can carry risks of urinary tract infection, hematuria, stones, cancer, and urethral erosion. The patient considers and decides against an indwelling catheter and off-label PTNS; the clinician determines she is a good candidate for onabotulinumtoxinA injections. Because she is voiding volitionally, a total of 100U of onabotulinumtoxinA is used. She reports a substantial response to the treatment on follow-up.

Appendix 4 Case 2 Case 2 is a 68-year-old man with an SCI from a motor vehicle collision 8 years earlier. He has hypertension and diabetes. He has a C6 injury, with American Spinal Injury Association Impairment Scale grade D. He lives with his wife who assists with his care, and he has an aide come in for 1h/d. When last checked 12 months earlier, his postvoid residual volume was low. He is on oxybutynin 5mg 3 times a day.

Complaint and evaluation He voids volitionally but has new onset UI and recurrent urinary tract infections over the last 6 months. On digital rectal examination, he has a 45-g prostate that is moderately enlarged. Urinalysis is within normative limits, and his postvoid residual volume is 250mL.

Initial treatment The treating urologist considers tamsulosin, mirabegron, antimuscarinics, botulinum neurotoxin injections, and SNM. However, because this is an older patient, the clinician must consider the possibility of an obstruction. The patient is treated empirically with tamsulosin, and his postvoid residual volume decreases to 150mL, but he remains symptomatic. Urodynamics are consistent with detrusor overactivity and bladder outlet obstruction, with a low peak flow of 6mL/s and an elevated detrusor pressure at peak flow of 73cm H2O. His treatment options are limited because of the obstruction, and he is not willing to consider an indwelling catheter; the obstruction minimizes therapies aimed solely at OAB/detrusor overactivity.

Follow-up The clinician explains to the patient that his treatment must be multistep. First they must address the obstruction. If, after that, his detrusor overactivity does not normalize, additional examination would be warranted. The clinician explains that approximately 60% of men with lower urinary tract symptoms who have detrusor overactivity and bladder outlet obstruction on urodynamics will see improvement of the lower urinary tract dysfunction once the obstruction is removed. Other options would then include an antimuscarinic or mirabegron; if he fails those, he would then be a candidate for a third-tier option, including PTNS, SNM, and onabotulinumtoxinA.

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S354 83. Scheepens WA, Van Koeveringe GA, De Bie RA, Weil EH, Van Kerrebroeck PE. Long-term efficacy and safety results of the two-stage implantation technique in sacral neuromodulation. BJU Int 2002;90:840-5. 84. Siegel SW, Catanzaro F, Dijkema HE, et al. Long-term results of a multicenter study on sacral nerve stimulation for treatment of urinary urge incontinence, urgency-frequency, and retention. Urology 2000; 56(6 Suppl 1):87-91. 85. Linsenmeyer TA. Use of botulinum toxin in individuals with neurogenic detrusor overactivity: state-of-the-art review. J Spinal Cord Med 2013;36:402-19. 86. de Se`ze M, Ruffion A, Haab F, et al. [Patient follow-up after botulinum toxin intradetrusor injection: proposal for management in neurogenic patients] [French]. Ann Readapt Med Phys 2008;51:315-21. 87. Knuepfer S, Juenemann KP. Experience with botulinum toxin type A in the treatment of neurogenic detrusor overactivity in clinical practice. Ther Adv Urol 2014;6:34-42. 88. Shakeri S, Mohammadian R, Aminsharifi A, et al. Success rate and patients’ satisfaction following intradetrusor disport injection in patients with detrusor overactivity: a comparative study of idiopathic and neurogenic types of detrusor overactivity. Urol J 2014;11:1289-95. 89. Yonnet GJ, Fieldstad AS, Carlson NG, Rose AW. Advances in the management of neurogenic detrusor overactivity in multiple sclerosis. Int J MS Care 2013;15:66-72. 90. Cruz F, Herschorn F, Aliotta P, et al. Efficacy and safety of onabotulinumtoxinA in patients with urinary incontinence due to neurogenic detrusor overactivity: a randomised, double-blind, placebo-controlled trial. Eur Urol 2011;60:742-50. 91. Ginsberg D, Gousse A, Keppenne V, et al. Phase 3 efficacy and tolerability study of onabotulinumtoxinA for urinary incontinence from neurogenic detrusor overactivity. J Urol 2012;187:2131-9. 92. BOTOX (onabotulinumtoxinA) [prescribing information]. Irvine: Allergan; 2013.

D.A. Ginsberg et al 93. DYSPORT (abotulinumtoxinA) [prescribing information]. Wrexham: Ipsen Biopharm; 2009. 94. IncobotulinumtoxinA (XEOMIN) [prescribing information]. Greensboro: Merz Pharmaceuticals; 2014. 95. RimabotulinumtoxinB (MYOBLOC) [prescribing information]. South San Francisco: Solstice Neurosciences; 2010. 96. Ginsberg D, Cruz F, Herschorn S, et al. OnabotulinumtoxinA is effective in patients with urinary incontinence due to neurogenic detrusor overactivity [corrected] regardless of concomitant anticholinergic use or neurologic etiology. Adv Ther 2013;30: 819-33. 97. Ghalayini IF, Al-Ghazo MA, Elnasser ZA. Is efficacy of repeated intradetrusor botulinum toxin type A (Dysport) injections dose dependent? Clinical and urodynamic results after four injections in patients with drug-resistant neurogenic detrusor overactivity. Int Urol Nephrol 2009;41:805-13. 98. Becher K, Oeke M, Grass-Kapanke B, et al. Improving the health care of geriatric patients: management of urinary incontinence: a position paper. Z Gerontol Geriatr 2013;46:456-64. 99. Kearns JT, Esposito D, Dooley B, Frim D, Gundeti MS. Urodynamic studies in spinal cord tethering. Childs Nerv Syst 2013;29: 1589-600. 100. Wolfe-Christensen C, Manolis A, Guy WC, et al. Bladder and bowel dysfunction: evidence for multidisciplinary care. J Urol 2013;190: 1864-8. 101. Stewart MA. Effective physician-patient communication and health outcomes: a review. Can Med J 1995;152:1423-33. 102. Schabert VF, Bavendam T, Goldberg EL, Trocio JN, Brubaker L. Challenges for managing overactive bladder and guidance for patient support. Am J Manag Care 2009;15(4 Suppl):A118-22. 103. Gablofen (baclofen injection) [prescribing information]. Hazelwood; Mallinckrodt Brand Pharmaceuticals; 2013.

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Neurogenic detrusor overactivity

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S356

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Neurogenic detrusor overactivity

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S357.e1 Supplemental Table S1

D.A. Ginsberg et al Device/drug status information

Generic Name

Trade Name

Dose

Route of Administration

Darifenacin

Enablex

Oral tablet

Desipramine Doxepin

Norpramin Sinequan

Fesoterodine Imipramine Mirabegron

Toviaz Tofranil Myrbetriq

Nortriptyline OnabotulinumtoxinA

Pamelor, generic Botox

Oxybutynin chloride

Ditropan XL

Oxybutynin chloride

Gelnique

Solifenacin

VESIcare

Tolterodine tartrate Tolterodine tartrate Trospium chloride Trospium chloride

Detrol Detrol LA Sanctura Sanctura XR

Starting dose is 7.5mg once daily. May be increased to 15mg once daily based on response. For depression: usual adult dose is 200mg daily. For depression: starting dose of 75mg once daily. May be increased or decreased up to 300mg daily. 2mg twice daily. May be lowered to 1mg twice daily. For depression, initially, 75mg/d increased to 150mg/d. Starting dose of 25mg once daily. Dose may be increased to 50mg once daily based on individual patient efficacy and tolerability. For depression: normative adult dose is 25mg, 3 or 4 times daily. For OAB: total dose of 100U as 0.5-mL injections across 20 sites into the detrusor. For NDO: total dose of 200U as 1-mL injections across 30 sites into the detrusor. Starting dose is 5 or 10mg once daily. May be adjusted in 5-mg increments up to a maximum of 30mg/d. Contents of 1 sachet should be applied once daily to dry, intact skin on the abdomen, upper arms/shoulders, or thighs. 5mg once daily. If well tolerated, dose may be increased to 10mg once daily. 2mg twice daily. May be lowered to 1mg twice daily. 4mg once daily may be lowered to 2mg daily. 20mg twice daily. 60mg once daily.

Oral tablets Oral capsule Oral tablet Oral tablets Oral tablet

Oral capsules, oral solution Single-use vial for injection

Oral tablet Gel Oral tablets Oral Oral Oral Oral

tablet capsules tablet tablet

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