improving outcomes in patients with refractory idiopathic ... · involve a disturbance in storage...

$: Improving Outcomes in Patients with Refractory Idiopathic ... · involve a disturbance in storage and emptying of the bladder. NDO is a urodynamic condition, defined as uninhibited,$
© 2015 Paradigm Medical Communications, LLC, except where noted.

Improving Outcomes in Patients with Refractory Idiopathic and Neurogenic

Detrusor Overactivity: Management Strategies

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

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


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.

Keywords

Urinary bladder; neurogenic; urinary incontinence; lower urinary tract symptoms; spinal cord

diseases; botulinum toxins, type A

Abbreviations

FDA, US Food and Drug Administration

HRQOL, health-related quality of life

MS, multiple sclerosis

NDO, neurogenic detrusor overactivity

NGB, neurogenic bladder

NLUTD, neurogenic lower urinary tract dysfunction

OAB, overactive bladder

PTNS, percutaneous (or posterior) tibial nerve stimulation

SCI, spinal cord injury

SNM, sacral neuromodulation

UI, urinary incontinence

UTI, urinary tract infection


INTRODUCTION

Neurogenic detrusor overactivity (NDO) and refractory idiopathic overactive bladder (OAB) are

lower urinary tract dysfunctions (LUTDs) commonly seen in rehabilitation settings. Common

populations affected by these disorders include patients with multiple sclerosis (MS), spinal

cord injury (SCI), Parkinson’s 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 (NGB) involves abnormal bladder function and/or 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, 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 as well as to the lower tract, resulting in urinary tract

infections (UTIs)7,8 or kidney and/or bladder stones.8 Historically, renal failure was the leading

cause of death in patients with spinal cord injury. However, earlier diagnosis and advances in

treatment of 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’s disease, but 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 post-

stroke UI is negatively associated with 2-year survival rates, worsened disability as measured by

the Barthel index, and increased rates of institutionalization.12 In fact, urinary incontinence is a

powerful predictor for whether stroke patients can be discharged to home from an inpatient

setting.13 UI has also been associated with an increased risk of falls and fractures in the elderly14

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 (HRQOL) is significant,17-20 and NDO

with UI causes a significantly greater effect on HRQOL 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 sleep23 and sexual activity24 and a restriction of social

activities due to fear of UI or because of the need for frequent voids.22 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, healthcare providers, and equipment, as

well as 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 (Figure 1).9

Consequently, NLUTD results from any disturbance in the nervous systems that control the

lower urinary tract. tract. Disruption of the connection between the pontine micturition center

and the sacral cord (i.e., 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 urinary

incontinence. 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).


Figure 1. Neural Control of Micturition

Photo Credit: Blarb/Shutterstock.com.

The 2 most common causes of NDO are MS and SCI; other common causes include Parkinson’s

disease and stroke.20 As seen in Table 1, a wide range of neurologic conditions have been

associated with NDO.31 Supraspinal neurologic diseases, such as Parkinson’s disease and

cerebral palsy, occur above the pontine micturition center and generally cause NDO with

synergistic voiding (e.g., no detrusor-sphincter dyssynergia). Suprasacral injuries involving the

spinal cord result in NDO with detrusor-sphincter dyssynergia, as well as an increased risk for

other urologic complications such as hydronephrosis, vesicourethral reflux, or 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.


Table 1. Neurologic Conditions Associated With NDO

Brain Spinal Cord

Peripheral Nervous

System and

Neuromuscular Junction

Cerebellar ataxia Acquired immune

deficiency syndrome Pernicious anemia Diabetic neuropathy

Cerebral palsy Ankylosing spondylosis

and disk disease Poliomyelitis Myasthenia gravis

Dementia Guillain-Barré syndrome Spinal cord injury Pelvic plexus injury

Multiple system atrophy Herpes zoster Tabes dorsalis

Neoplasms Lyme disease Tethered cord syndrome

and short filum terminale

Parkinson’s disease Multiple sclerosis Transverse myelitis

Stroke Myelomeningocele Tropical spastic

paraparesis

Republished with permission of Haymarket Media Inc, from Chancellor MB. Current treatment

options for neurogenic bladder dysfunction. Renal and Urology News July 1, 2012. Permission

conveyed through Copyright Clearance Center, Inc.31

Patients with NDO often present with UI, although the symptoms vary.33 An estimated 23.6% of

patients with stroke, one-third of patients with Parkinson’s 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 due to NDO, is also high—affecting 68% of those with SCI, 37% to 72% of patients

with MS, and 35% to 70% of patients with Parkinson’s 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, although 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’s disease can be particularly challenging as they can have UI, urgency, and


incomplete emptying combined with the inability to move rapidly enough to get to the toilet.

There are also non-urologic causes for UI. For example, some patients may not be able to

communicate their need to urinate—whether owing to aphasia, dysfluency, dysphonia, or even

language barriers. They may have impaired or decreased mobility, poor dexterity, or confusion

and delirium. Older patients can have non-neurologic as well as neurologic urinary issues (e.g.,

normal-pressure hydrocephalus.36) Women might have concomitant stress urinary

incontinence, prolapse, and/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 non-neurologic etiologies, such as

bladder abnormalities—bladder cancer, bladder stones, or interstitial cystitis; prostate or

urethral abnormalities, prostate cancer, or urethral stone (in men); pelvic prolapse (in women);

or stress urinary incontinence.37 Symptoms can also stem from urogenital infections, such as

bacterial cystitis, prostatitis, or urethritis.

In contrast to 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, and neurologic), urinalysis and urine culture,

and blood chemistry, as well as 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; QOL; social history, including smoking and drug

or alcohol use as well as hereditary or familial risk factors. Physical examination needs to note

sensations from S2-S5 on both sides—presence of sensation, type of sensation, reflexes; anal

sphincter tone; and prostate exam (men) or evaluation of pelvic organ prolapse (women). The

urologic history should include information about initiation of micturition—normal, precipitate,

reflex, strain, Credé; 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 (e.g.,

parkinsonism, MS, stroke), mental status, and onset and evolution of any neurologic symptoms;

spasticity, mobility, hand function, and presence of autonomic dysreflexia.9 Helpful studies


include a bladder and/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 paper. Many MS patients, especially female patients, 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 UDS would be indicated.

However, symptoms and the physical exam 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 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 neurogenic lower urinary tract

dysfunction are by the European Association of Urology in 2011.9 In order of importance, the

EAU 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 QOL by relieving symptoms.9

Table 2 lists the range of available guidelines related to diagnosis and management of bladder

problems in adults.9,33,45-47 It should be noted that not all treatments recommended for OAB are

equally effective or beneficial for patients with NDO.


Table 2. Guidelines for OAB and NDO

2014 AUA/SUFU Guideline on OAB in adults: Gormley 201246

2013 EAU Guidelines on UI: EAU uroweb45

2012 USA, MSAA Consensus statement on improving bladder care in MS/SCI: Ellsworth 201233

2011 EAU Guideline on neurogenic lower urinary tract dysfunction: Pannek 20119

2006 PVA Clinical practice guidelines for bladder management in SCI: PVA 200647

AUA, American Urological Association; SUFU, Society for Urodynamics, Female Pelvic Medicine &

Urogenital Reconstruction; USA, United Spinal Association; MSAA, Multiple Sclerosis Association of

America; PVA, Paralyzed Veterans of America

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 number of UTIs and AD. For OAB patients,

success is determined by patient satisfaction, which can objectively be evaluated by a variety of

validated questionnaires. For NDO patients, 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 like pyridium can determine if there is UI. Evaluating the number of UTIs,

episodes of autonomic dysreflexia in patients with SCI, can also be used to define success.

Qualitative outcomes such as community participation, self-esteem, sleep quality and quantity,

mood, and other measures of QOL 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 prior to initiation of therapy

First-line Treatments

According to the EAU guidelines for NLUTD, first-line options include a range of noninvasive

conservative treatments, such as behavioral modification techniques, lifestyle modifications,

prompted voiding and 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 (AUA/SUFU) 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 EAU and AUA/SUFU guidelines, first, second and third line treatments are tiered

in order of invasiveness, and, as per the guidelines, are recommended to be used in a stepwise

approach.

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 bowel; 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, and peripheral temporary

electrostimulation—may be beneficial to a small group of patients, such as 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 first-line 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 such as cerebrovascular disease, Parkinson’s disease, multiple system

atrophy, dementia, and cerebral palsy, as well as 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 includes

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.

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. While 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 do patients with OAB—e.g., 30 mg oxybutynin, 8 mg tolterodine

extended release, or 90 mg trospium—which can lead to increased incidence of adverse

effects.9,32,56,57 American Urological Association guidelines for OAB recommend the use of once-

daily, 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, as well as alternative routes of administration—transdermally or 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, such as trospium chloride, which has 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 narrow-angle 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 CIC; and used with caution in patients using other medications with

anticholinergic properties or in frail OAB/NDO patients.46 Although long-term persistence with

pharmacotherapy is required for consistent results, adherence after 3 months is relatively poor

due to bothersome side effects such as dry mouth and constipation.64 Clinicians need to

manage constipation and dry mouth before abandoning effective antimuscarinic therapy.46

Although antimuscarinic agents do not have an FDA-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, and darifenacin—in this patient

population.9,32,55,65

The detrusor muscle contains beta-adrenoceptors. Human bladder and urothelium contain

beta1-, beta2-, and beta3-adrenoceptors66; 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 normal and neurogenic bladders. Mirabegron

is the first and only beta3-agonist with FDA approval for OAB. It has minimal intrinsic activity on

beta1 or beta2 adrenoceptors, and thus minimizes or eliminates the undesirable adverse

effects associated with them, such as increased heart rate and muscle tremors.70 The incidence

of dry mouth associated with mirabegron is similar to that with placebo and reportedly

threefold 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 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 FDA-

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 (or posterior) 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 (or posterior) Tibial Nerve Stimulation (PTNS). 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 FDA-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 MS patients.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 FDA-

approved for OAB and urge incontinence and may be beneficial for refractory patients with

moderately severe baseline UI and urinary frequency.

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 NGB/NDO.46,78

SNM involves stimulation of the 3rd sacral foramen—the nerve most responsible for bladder

function (Figure 2). The treatment is performed in stages. The initial test phase identifies


patients who respond to temporary percutaneous nerve evaluation. Patients who respond—

defined as those who demonstrate at least a 50% improvement in target symptoms—can 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 MRI has not been

established for patients with this device and is not recommended by the manufacturer.

Figure 2: Sacral Neuromodulation

Image reprinted with permission from medicalimages.com.

Although SNM is a well-established and widely accepted treatment for refractory non-

neurogenic LUTD, its use in patients with NLUTD is unclear,79 and 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 is

generally limited to those patients who do not have progressive disease—specifically, 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 upon 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’s 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

NGB 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 (non-neurogenic) 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 did

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 FDA-

approved for NDO, as well as for urge incontinence and OAB. It is an effective alternative for

NDO patients who fail pharmacotherapy,40,85 and is safe and effective in catheterized refractory

NDO patients.9,86-89 The EAU guidelines note that “botulinum toxin injection in the detrusor is

the most effective minimally invasive treatment to reduce neurogenic detrusor overactivity”.9

Injections with onabotulinumtoxinA have been shown to significantly improve QOL.90 The most

common adverse effects associated with onabotulinumtoxinA treatment include UTIs, 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 such as spasticity, as 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 20-30 injections of 0.5-1 mL (approximately 6-10 U) onabotulinumtoxinA in

the bladder, located 1 cm apart and 2 mm into the detrusor (Figure 3). Go to

www.paradigmmc.com/342injvid to view a short video of one of the authors performing the

procedure.


Figure 3: Botulinumtoxin Injections Into the Bladder

Image reprinted with permission from Ginsberg D et al. J Urol 2012;187(2):2131-9.91

The FDA approved doses are 200 U for NDO and 100 U for OAB. However for NDO/NGB

patients that continue to void volitionally—often MS and Parkinson’s disease—the 100 U dose

is usually considered to reduce the risk of post-injection retention requiring CIC. 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 FDA-approval for NDO as well as 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 FDA 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 200 units (n=227), onabotulinumtoxinA 300 units (n=223), or placebo


(n=241). 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, and volume at first involuntary detrusor contraction, as well as QOL as measured

by the Incontinence QOL 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 (Figure 4). In the first trial, the reduction

in UI episodes per week was 21.8 and 19.4 among patients receiving onabotulinumtoxinA

injections, 200 units and 300 units, 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

units and 300 units, 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 (Figure 5).92 At week 6, treatment with onabotulinumtoxinA led to

significant improvements in maximum cystometric capacity, maximum detrusor pressure during

the first involuntary detrusor contraction, and I-QOL compared with placebo, as well as

significantly longer median time to patient request for retreatment: 36-42 weeks versus 13

weeks, respectively. Further, both trials noted a significantly greater 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-unit dose over the 200-unit dose, and there was a greater risk of urinary

retention reported with the higher dose, resulting in approval for the 200-unit dose.90-92,96

Figure 4. Mean Change From Baseline in Weekly UI Episodes in MS and SCI

Reprinted with permission from Ginsberg D et al. Adv Ther 2013;30(9):819-33.96


Figure 5. OnabotulinumtoxinA Phase 3 Trials in NDO: Urodynamics

Data from BOTOX [Prescribing Information]. Irvine, CA: Allergan, Inc; 2013.92

The most frequently reported adverse events noted within the first 12 weeks after

intradetrusor injection were UTI, seen in 24% of patients treated with onabotulinumtoxinA 200

units 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 self-

catheterization with potential patients before beginning these treatments and make sure they

are willing and able to initiate catheterization post-treatment, if required, for urinary

retention.92

AbobotulinumtoxinA has also been evaluated and shown to be effective, although it does not

have FDA approval for NDO. A trial involving 22 patients with NDO—13 men and 9 women—

evaluated successive doses of abobotulinumtoxinA injected repeatedly into the bladder. Twelve

patients received 500 units, and 10 received 1000 units. There was a constant effect following

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, PHYSICIAN-PATIENT COMMUNICATION

Optimal management of patients with NDO requires a multidisciplinary team approach.98-100

Typically, the primary care 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 healthcare 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—

from transportation, acquiring durable medical equipment or materials, and/or negotiating

insurance, among others. 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 SCI patients and 26% of MS patients.

More than half of the MS patients (53%) had been seen by a neurologist, compared with 18.5%

of patients with SCI. However, fewer than 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 QOL

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 HRQOL.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 expectations—

not necessarily treatment failure—despite 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.”

In summary, both NDO and OAB are common among patients in rehabilitation settings, and

both can have significant negative impact on medical stability and QOL. These patients need to

be differentially identified and evaluated by the appropriate clinician(s) and treated accordingly

(see Case Studies 1 and 2, below). In certain cases, patients can be treated empirically based on

clinical presentation, but in the majority of 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, and

botulinumtoxin injections. Only the latter is specifically approved for management of NDO.


Case Study 1

A 44-year-old woman, gravida 3 para 2,

with MS diagnosed at age 33 years, who

uses a cane when walking, although 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

about 1% of patients.103

Complaint and Evaluation: Her presenting

complaints are urinary frequency/urgency

and worsening UI. She is currently taking

solifenacin 5 mg without optimal response. Her exam is unremarkable, Urinalysis: white blood

count, 6-10; postvoid residual volume: 95 mL.

Initial treatment: The treating clinician considers numerous treatment options: increasing the

dose of solifenacin from 5 to 10 mg; 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, so 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 (SP) tubes, and notes that these options may be ideal for a

group of patients, but can carry risks of UTI, 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 100 units of onabotulinumtoxinA are used. She reports a

substantial response to the treatment on follow-up.


Case Study 2

A 68-year-old male with an SCI from a motor vehicle accident 8

years earlier. He has hypertension and diabetes. He’s a C6,

American Spinal Injury Association Impairment Scale D. He lives

with his wife who assists with his care, and he has an aide

come in for 1 hour a day. When last checked 12 months earlier,

his postvoid residual volume was low. He is on oxybutynin 5 mg

TID.

Complaint and Evaluation: He voids volitionally but has new

onset UI and recurrent UTIs over the past 6 months. On digital

rectal examination, he has a 45-g prostate that is moderately

enlarged. Urinalysis is within normal limits and his postvoid residual volume is 250 mL.

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 150 mL, but he remains

symptomatic. Urodynamics are consistent with detrusor overactivity and bladder outlet

obstruction with a low peak flow of 6 mL/s and an elevated detrusor pressure at peak flow of

73 cm H2O. His treatment options are limited because of the obstruction—he is not willing to

consider an indwelling catheter; and 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.


Device/drug status information

Generic name

Trade name(s)

Dose

Route of

administration

Darifenacin Enablex Starting dose is 7.5 mg once daily. May be

increased to 15 mg once daily based on

response.

Oral tablet

Desipramine Norpramin For depression: usual adult dose is 200 mg

daily

Oral tablets

Doxepin Sinequan For depression: starting dose of 75 mg once

daily. May be increased or decreased up to

300 mg daily

Oral capsule

Fesoterodine Toviaz 2 mg twice daily. May be lowered to 1 mg

twice daily

Oral tablet

Imipramine Tofranil For depression, initially, 75 mg/day

increased to 150 mg/day

Oral tablets

Mirabegron Myrbetriq Starting dose of 25 mg once daily. Dose may

be increased to 50 mg once daily based on

individual patient efficacy and tolerability

Oral tablet

Nortriptyline Pamelor, generic For depression: normal adult dose is 25 mg 3

or 4 times daily

Oral capsules, oral

solution

OnabotulinumtoxinA Botox For OAB: total dose of 100 units as 0.5 mL

injections across 20 sites into the detrusor

For NDO: total dose of 200 units as 1 mL

injections across 30 sites into the detrusor

Single-use vial for

injection

Oxybutynin chloride Ditropan XL Starting dose is 5 or 10 mg once daily. May

be adjusted in 5-mg increments up to a

maximum of 30 mg/d.

Oral tablet

Oxybutynin chloride Gelnique Contents of one sachet should be applied

once daily to dry, intact skin on the

abdomen, upper arms/shoulders, or thighs

Gel

Solifenacin VESIcare 5 mg once daily. If well tolerated, dose may

be increased to 10 mg once daily

Oral tablets

Tolterodine tartrate Detrol 2 mg twice daily. May be lowered to 1 mg

twice daily.

Oral tablet

Tolterodine tartrate Detrol LA 4 mg once daily may be lowered to 2 mg

daily

Oral capsules

Trospium chloride Sanctura 20 mg twice daily Oral tablet

Trospium chloride Sanctura XR 60 mg once daily Oral tablet


References

1. International Continence Society. Terminology.

Available at: www.ICS.org/search/defining-OAB.

Accessed January 8, 2015.

2. Manack A, Motsko SP, Haag-Molkenteller C, et al.

Epidemiology and healthcare utilization of neurogenic

bladder patients in a US claims database. Neurourol

Urodyn 2011;30(3):395-401.

3. Abrams P, Cardozo L, Fall M, et al, for the

Standardisation Sub-committee of the International

Continence Society. The standardisation of

terminology of lower urinary tract function: report

from the Standardisation Sub-committee of the

International Continence Society. Neurourol Urodyn

2002;21(2):167-78.

4. Wein AJ, Rovner ES. Definition and epidemiology of

overactive bladder. Urology 2002;60(5 suppl 1):7-12.

5. Samson G, Cardenas DD. Neurogenic bladder in

spinal cord injury. Phys Med Rehabil Clin N Am

2007;18(2):255-74.

6. Flood HD, Ritchey ML, Bloom DA, Huang C, McGuire

EJ. Outcome of reflux in children with myelodysplasia

managed by bladder pressure monitoring. J Urol

1994;152(5 pt 1):1574-7.

7. Jahromi MS, Mure A, Gomez CS. UTIs in patients

with neurogenic bladder. Curr Urol Rep

2014;15(9):433.

8. Gormley EA. Urologic complications of the

neurogenic bladder. Urol Clin North Am

2010;37(4):601-7.

9. Pannek J, Stohrer M, Blok B, et al. European

Association of Urology. Guidelines on neurogenic

lower urinary tract dysfunction. 2011. Available at:

www.uroweb.org/gls/pdf/17_Neurogenic%20LUTS.

pdf. Accessed February 6, 2015.

10. Beeckman D, Van Lancker A, Van Hecke A,

Verhaeghe S. A systematic review and meta-analysis of

incontinence-associated dermatitis, incontinence, and

moisture as risk factors for pressure ulcer

development. Res Nurs Health 2014;37(3):204-18.

11. Gefen A. From incontinence associated dermatitis

to pressure ulcers. J Wound Care 2014;23(7):345.

12. Patel M, Coshall C, Rudd AG, Wolfe CD. Natural

history and effects on 2-year outcomes of urinary

incontinence after stroke. Stroke 2001;32(1):122-7.

13. Brittain KR, Peet SM, Castleden CM. Stroke and

incontinence. Stroke 1998;29(2):524-8.

14. Hedman AM, Fonad E, Sandmark H. Older people

living at home: associations between falls and health

complaints in men and women. J Clin Nurs

2013;22(19-20):2945-52.

15. Lahmann NA, Heinze C, Rommel A. Falls in German

hospitals and nursing homes 2006-2013. Frequencies,

injuries, risk assessment, and preventive measures [in

German]. Bundesgesundheitsblat

Gesundheitsofrschung Gesundheitsschutz

2014;57(6):650-9.

16. Luppa M, Luck T, Weyerer S, Konig H-K, Riedel-

Heller SG. Gender differences in predictors of nursing

home placement in the elderly: a systematic review.

Int Psychogeriatr 2009;21(6):1015-25.

17. Haab F. Chapter 1: The conditions of neurogenic

detrusor overactivity and overactive bladder.

Neurourol Urodyn 2014;33(suppl 3):S2-5.

18. Irwin DE, Milsom I, Kopp Z, Abrams P, Cardozo L.

Impact of overactive bladder symptoms on

employment, social interactions and emotional well-

being in six European countries. BJU Int 2006;97(1):96-

100.

19. Tang DH, Colayco D, Piercy J, Patel V, Globe D,

Chancellor MB. Impact of urinary incontinence on

health-related quality of life, daily activities, and

healthcare resource utilization in patients with

neurogenic detrusor overactivity. BMC Neurol

2014;14:74.

20. Tapia CI, Khalaf K, Berenson K, Globe D, Chancellor

M, Carr LK. Health-related quality of life and economic

impact of urinary incontinence due to detrusor

overactivity associated with a neurologic condition: a

systematic review. Health Qual Life Outcomes

2013;11:13.

21. Zorn BH, Montgomery H, Pieper K, Gray M, Steers

WD. Urinary incontinence and depression. J Urol

1999;162(1):82-4.

22. Stewart WF, Van Rooyen JB, Cundiff GW, et al.

Prevalence and burden of overactive bladder in the

United States. World J Urol 2003;20(6):327-36.

23. Shaw C. A systematic review of the literature on

the prevalence of sexual impairment in women with

urinary incontinence and the prevalence of urinary


leakage during sexual activity. Eur Urol

2002;42(5):432-40.

24. Fultz NH, Herzog AR. Self-reported social and

emotional impact of urinary incontinence. J Am

Geriatr Soc 2001;49(7):892-9.

25. Reeves P, Irwin D, Kelleher C, et al. The current and

future burden and cost of overactive bladder in five

European countries. Eur Urol 2006;50(5):1050-7.

26. Onukwugha E, Zuckerman IH, McNally D, Coyne KS,

Vats V, Mullins CD. The total economic burden of

overactive bladder in the United States: a disease-

specific approach. Am J Manag Care 2009;15(4

suppl):S90-7.

27. Coyne KS, Wein A, Nicholson S, Kvasz M, Chen CI,

Milsom I. Economic burden of urgency urinary

incontinence in the United States: a systematic review.

J Manag Care Pharm 2014;20(2):130-40.

28. Hu TW, Wagner TH, Bentkover JD, Leblanc K, Zhou

SZ, Hunt T. Estimated economic costs of overactive

bladder in the United States. Urology

2003;61(6):1123-8.

29. Hu TW, Wagner TH, Bentkover JD, Leblanc K, Zhou

SZ, Hunt T. Costs of urinary incontinence and

overactive bladder in the United States: a comparative

study. Urology 2004;63(3):461-5.

30. Mullins CD, Subak LL. New perspectives on

overactive bladder: quality of life impact, medication

persistency, and treatment costs. Am J Manag Care

2005;11(4 suppl):S101-2.

31. Chancellor MB. Part II. Current treatment options

for neurogenic bladder dysfunction. Renal Neurol

News. July 1, 2012. Available at: www.renaland

urologynews.com/part-ii-current-treatment-options-

for-neurogenic-bladder-dysfunction/article/

248201/2/. Accessed January 8, 2015.

32. Kennelly MJ, DeVoe WB. Overactive bladder:

pharmacologic treatments in the neurogenic

population. Rev Urol 2008;10(3):182-91.

33. Ellsworth PI, Coyne PK, Esquenazi A, et al.

Consensus statement on neurogenic detrusor

overactivity: multiple sclerosis and spinal cord injury.

UroToday Intl J 2012;5(suppl 1):1-18.

34. Ruffion A, Castro-Diaz D, Patel H, et al. Systematic

review of the epidemiology of urinary incontinence

and detrusor overactivity among patients with

neurogenic overactive bladder. Neuroepidemiology

2013;41(3-4):146-55.

35. Wein AJ, Dmochowski RR. Campbell-Welsh Urology

10th ed, Philadelphia PA: Elsevier Saunders;

2012;1909-46.

36. Campos-Juanatey F, Gutierrez-Banos JL, Portillo-

Martin JA, Zubillaga-Guerrero S. Assessment of the

urodynamic diagnosis in patients with urinary

incontinence associated with normal pressure

hydrocephalus [published online ahead of print April

12, 2014]. Neurourol Urodyn doi:10.1002/nau.22600.

37. Rosenberg MT, Newman DK, Tallman CT, Page SA.

Overactive bladder: recognition requires vigilance for

symptoms. Cleve Clin J Med 2007;74(suppl 3):S21-9.

38. Chancellor MB, Anderson RJ, Boone TB.

Pharmacotherapy for neurogenic detrusor

overactivity. Am J Phys Med Rehabil 2006;85(6):536-

45.

39. Harrington A, Bhandary A. Neurogenic detrusor

overactivity after spinal cord injury. Available at:

www.UPMCPhysicianResources.com/Rehab2010.

Accessed December 19, 2015.

40. Mehta S, Hill D, McIntyre A, et al. Meta-analysis of

botulinum toxin a detrusor injections in the treatment

of neurogenic detrusor overactivity after spinal cord

injury. Arch Phys Med Rehabil 2011;94(8):1473-81.

41. Abrams P, Andersson KE, Birder L, et al, for the

Members of Committees; Fourth International

Consultation on Incontinence. Fourth International

Consultation on Incontinence Recommendations of

the International Scientific Committee: Evaluation and

treatment of urinary incontinence, pelvic organ

prolapse, and fecal incontinence. Neurourol Urodyn

2010;29(1):213-40.

42. Bates D, Burks J, Globe D, et al. Development of a

short form and scoring algorithm from the validated

actionable bladder symptom screening tool. BMC

Neurol 2013;13:78.

43. Campea S. Autonomic dysreflexia in spinal cord

injury. In: Gonzalez-Fernandez M, ed. PM&R

Knowledge NOW November 11, 2011.

http://me.aapmr.org/kn/article.html?id=2. Accessed

January 8, 2015.

44. Weld KJ, Dmochowski RR. Association of level of

injury and bladder behavior in patients with post-

traumatic spinal cord injury. Urology 2000;55(4):490-

494.

45. European Association of Urology (EAU); Lucas MG,

Bedretdinova D, Bosch JLHR, et al. Guidelines on

urinary incontinence (2013). Available at: www.


uroweb.org/gls/pdf/19_Urinary_Incontinence_LR.pdf.

Accessed December 19, 2015.

46. Gormley EA, Lightner DJ, Burgio KL, et al, for the

American Urological Association; Society of

Urodynamics, Female Pelvic Medicine & Urogenital

Reconstruction. Diagnosis and treatment of overactive

bladder (non-neurogenic) in adults: AUA/SUFU

guideline. J Urol 2012;188(6 suppl):2455-63. Updated

version available at: www.auanet.org/education/

guidelines/overactive-bladder.cfm. Accessed January

8, 2015.

47. Paralyzed Veterans of America. Bladder

management for adults with spinal cord injury: a

clinical practice guideline for health-care providers.

2006. Washington, DC. Available at: www.pva.org.

Accessed January 8, 2015.

48. McClurg D, Ashe RG, Marshall K, Lowe-Strong AS.

Comparison of pelvic floor muscle training,

electromyography biofeedback, and neuromuscular

electrical stimulation for bladder dysfunction in people

with multiple sclerosis: a randomized pilot study.

Neurourol Urodyn 2006;25(4):337-46.

49. Newman DK, Wein AJ. Office-based behavioral

therapy for management of incontinence and other

pelvic disorders. Urol Clin North Am 2013;40(4):613-

35.

50. Yamaguchi O, Nishizawa O, Takeda M, et al.

Clinical Guidelines for overactive bladder. Int J Urol

2009;16(2):126-42.

51. Alhasso AA, McKinlay J, Patrick K, Stewart L.

Anticholinergic drugs versus non-drug active therapies

for overactive bladder syndrome in adults. Cochrane

Database Syst Rev 2006:Oct 18;(4):CD003193.

52. Borello-France D, Burgio KL. Nonsurgical treatment

of urinary incontinence. Clin Obstet Gynecol

2004;47(1):70-82.

53. Milne JL, Moore KN. Factors impacting self-care for

urinary incontinence. Urol Nurs 2006;26(1):41-51.

54. Wyndaele J-J. Conservative treatment of patients

with neurogenic bladder. Eur Urol Suppl 2008;7:557-

65.

55. Madersbacher H, Mürtz G, Stöhrer M. Neurogenic

detrusor overactivity in adults: a review on efficacy,

tolerability and safety of oral antimuscarinics. Spinal

Cord 2013;51(6):432-41.

56. Bennett N, O’Leary M, Patel AS, Xavier M, Erickson

JR, Chancellor MB. Can higher doses of oxybutynin

improve efficacy in neurogenic bladder? J Urol

2004;171(2 pt 1):749-51.

57. O’Leary M, Erickson JR, Smith CP, McDermott C,

Horton J, Chancellor MB.. Effect of controlled release

oxybutynin on neurogenic bladder function in spinal

cord injury. J Spinal Cord Med 2003;26(2):159-62.

58. Chancellor M, Boone T. Anticholinergics for

overactive bladder therapy: central nervous system

effects. CNS Neurosci Ther 2012;18(2):167-74.

59. Paquette A, Gou P, Tannenbaum C. Systematic

review and meta-analysis: do clinical trials testing

antimuscarinic agents for overactive bladder

adequately measure central nervous system adverse

events? J Am Geriatr Soc 2011;59(7):1332-9.

60. Wagg A, Verdejo C, Molander U. Review of

cognitive impairment with antimuscarinic agents in

elderly patients with overactive bladder. Int J Clin

Pract 2010;64(9):1279-86.

61. Wagg A, Dale M, Tretter R, Stow B, Compion G.

Randomised, multicenter, placebo-controlled, double-

blind crossover study investigating the effect of

solifenacin and oxybutynin in elderly people with mild

cognitive impairment: the SENIOR study. Eur Urol

2013;64(1):74-81.

62. Kay GG, Abou-Donia MB, Messer WS Jr., Murphy

DG, Tsao JW, Ouslander JG. Antimuscarinic drugs for

overactive bladder and their potential effects on

cognitive function in older patients. J Am Geriatr Soc

2005;53(12):2195-201.

63. Natalin R, Lorenzetti F, Dambros M. Management

of OAB in those over age 65. Curr Urol Rep

2013;14(5):379-85.

64. Chapple CR, Nitti VW, Khullar V, et al. Onset of

action of the β3-adrenoceptor agonist, mirabegron, in

phase II and III clinical trials in patients with overactive

bladder. World J Urol 2014;32(6):1565-72.

65. Krebs J, Pannek J. Effects of solifenacin in patients

with neurogenic detrusor overactivity as a result of

spinal cord lesion. Spinal Cord 2013;51(4):306-9.

66. Tyagi P, Thomas CA Yoshimura N, Chancellor MB.

Investigations into the presence of functional Beta1,

Beta2 and Beta3-adrenoceptors in urothelium and

detrusor of human bladder. Int Braz J Urol

2009;35(1):76-83.

67. Yamaguchi O. Beta3-adrenoceptors in human

detrusor muscle. Urology 2002;50(5 suppl 1):25-9.


68. Andersson KE, Martin N, Nitti V. Selective β3-

adrenoceptor agonists for the treatment of overactive

bladder. J Urol 2013;190(4):1173-80.

69. Igawa Y, Yamazaki Y, Takeda H, et al. Relaxant

effects of isoproterenol and selective beta3-

adrenoceptor agonists on normal, low compliant and

hyperreflexic human bladders. J Urol 2001;165(1):240-

4.

70. Nitti VW, Khullar V, van Kerrebroeck P, et al.

Mirabegron for the treatment of overactive bladder: a

prespecified pooled efficacy analysis and pooled safety

analysis of three randomized, double-blind, placebo-

controlled, phase III studies. Int J Clin Pract

2013;67(7):619-32.

71. Nitti VW, Auerbach S, Martin N, Calhoun A, Lee M,

Herschorn S. Results of a randomized phase III trial of

mirabegron in patients with overactive bladder. J Urol

2013;189(4):1388-95.

72. Caremel R, Loutochin O, Corcos J. What do we

know and not know about mirabegron, a novel β3

agonist, in the treatment of overactive bladder? Int

Urogynecol J 2014;25(2):165-70.

73. Myrbetriq [Prescribing information]. Northbrook

IL: Astellas Pharma US, Inc; 2014.

74. Murphy AM, Krlin RM, Goldman HB. Treatment of

overactive bladder: what is on the horizon? Int

Urogynecol J 2013;24(1):5-13.

75. Abrams P, Kelleher C, Staskin D, et al. Combination

treatment with mirabegron and solifenacin in patients

with overactive bladder: efficacy and safety results

from a randomized, double-blind, dose-ranging, phase

2 study (Symphony) [published online ahead of print

February 19, 2014]. Eur Urol

doi:10.1016/j.eururo.2014.02.012.

76. Kabay S, Kabay SC, Yucel M, et al. The clinical and

urodynamic results of a 3-month percutaneous

posterior tibial nerve stimulation treatment in patients

with multiple sclerosis-related neurogenic bladder

dysfunction. Neurourol Urodyn 2009;28(8):964-8.

77. de Sèze M, Raibaut P, Gallien P, et al.

Transcutaneous posterior tibial nerve stimulation for

treatment of the overactive bladder syndrome in

multiple sclerosis: results of a multicenter prospective

study. Neurourol Urodyn 2011;30(3):306-11.

78. Leong RK, De Wachter SG, van Kerrebroeck PE.

Current information on sacral neuromodulation and

botulinum toxin treatment for refractory idiopathic

overactive bladder syndrome: a review. Urol Int

2010;84(3):245-53.

79. Knupfer SC, Liechti MD, Mordasini L, et al. Protocol

for a randomized, placebo-controlled, double-blind

clinical trial investigating sacral neuromodulation for

neurogenic lower urinary tract dysfunction. BMC Urol

2014;14:65.

80. Chaabane W, Guillotreau I, Castel-Iacanal E, et al.

Sacral neuromodulation for treating neurogenic

bladder dysfunction: clinical and urodynamic study.

Neurourol Urodyn 2011;30(4):547-50.

81. Chen G, Liao L. Sacral neuromodulation for

neurogenic bladder and bowel dysfunction with

multiple symptoms secondary to spinal cord disease

[published online ahead of print September 16, 2014].

Spinal Cord doi:10.1038/sc.2014.157.

82. Foster RT Sr, Anoia EJ, Webster GD, Amundsen CL.

In patients undergoing neuromodulation for

intractable urge incontinence a reduction in 24-hr pad

weight after the initial test stimulation best predicts

long-term patient satisfaction. Neurourol Urodyn

2007;26(2):213-7.

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(9):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(5):402-19.

86. de Sèze M, Ruffion A, Haab F, et al. Patient follow-

up after botulinum toxin intradetrusor injection:

proposal for management in neurogenic patients [in

French]. Ann Readapt Med Phys 2008;51(4):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(1):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(1):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(2):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(4):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(2):2131-9.

92. BOTOX (onabotulinumtoxinA) [Prescribing

Information]. Irvine CA: Allergan, Inc.; 2013.

93. DYSPORT (abotulinumtoxinA) [Prescribing

Information]. Wrexham, UK: Ipsen Biopharm Ltd;

2009.

94. IncobotulinumtoxinA (XEOMIN) [Prescribing

Information]. Greensboro, NC: Merz Pharmaceuticals,

LLC; 2014.

95. RimabotulinumtoxinB (MYOBLOC) [Prescribing

information]. South San Francisco, CA: Solstice

Neurosciences, Inc; 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(9):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(4):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(5):456-64.

99. Kearns JT, Esposito D, Dooley B, Frim D, Gundeti

MS. Urodynamic studies in spinal cord tethering.

Childs Nerv Syst 2013;29(9):1589-600.

100. Wolfe-Christensen C, Manolis A, Guy WC, et al.

Bladder and bowel dysfunction: evidence for

multidisciplinary care. J Urol 2013;190(5):1864-8.

101. Stewart MA. Effective physician-patient

communication and health outcomes: a review. Can

Med J 1995;152(9):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, MO; Mallinckrodt Brand

Pharmaceuticals, Inc. 2013.

improving outcomes in patients with refractory idiopathic ... · involve a disturbance in storage...

Documents