Botulinum Toxin Injections for Neurogenic Detrusor Overactivity 

Updated: Mar 06, 2019
Author: Pamela I Ellsworth, MD; Chief Editor: Edward David Kim, MD, FACS 

Overview

Background

This topic addresses the use of botulinum toxin injections to treat neurogenic detrusor overactivity (NDO). Various neurologic conditions may cause detrusor overactivity and urinary incontinence. In select conditions, such as spinal cord injury, the attendant risk of upper tract deterioration exists as a result of pyelonephritis and increased intravesical pressure as a result of poor bladder compliance and detrusor sphincter dyssynergia.

Initial management of patients with detrusor overactivity related to a neurologic condition consists of behavioral therapy, when feasible, and anticholinergic therapy. In those patients with increased postvoid residuals, clean intermittent catheterization is often used in conjunction with anticholinergic therapy.

However, the side effects of anticholinergic therapy have led to poor compliance with long-term use. In attempts to improve the efficacy and tolerability of anticholinergic therapy, several newer therapies have been developed that are available in sustained-release formulations and variable doses.

Despite these modifications, patients whose response to anticholinergic therapy may be unsatisfactory in terms of either efficacy or tolerability exist. Historically, such individuals were faced with more invasive surgical interventions to lower detrusor pressure or promote continence, including bladder augmentation. Bladder augmentation is not without significant long-term risks, including infections, stones, malignancy, and perforation.

A form of botulinum toxin A known as onabotulinumtoxinA (BOTOX; Allergan, Irvine, CA) has been approved by the US Food and Drug Administration (FDA) for the treatment of urinary incontinence due to NDO in adults who have an inadequate response to or are intolerant of anticholinergic therapy.

Botulinum toxin A blocks neuromuscular transmission by binding to acceptor sites on motor or sympathetic nerve terminals, entering the nerve terminals, and inhibiting the release of acetylcholine. The inhibition occurs as the neurotoxin cleaves synaptosomal-associated protein 25 (SNAP-25), a protein critical to the successful docking and release of acetylcholine from presynaptic vesicles located within the nerve endings.

When injected into the muscle at therapeutic doses, botulinum toxin A produces partial chemical denervation of the muscle, resulting in a localized reduction in muscle activity. In addition, the muscle may atrophy, axonal sprouting may occur, and extra junctional acetylcholine receptors may develop. Evidence exists that reinnervation of the muscle may occur, thus slowly reversing the muscle denervation produced by botulinum toxin A.

Also proposed is that the effect of botulinum toxin A on detrusor overactivity may be related to its effect on sensory receptor expression in suburothelial fibers.[1] The expression of TRPV1, P2X3, substance P, and calcitonin gene-related peptide by these fibers has also been proposed to play a role in the pathophysiology of detrusor overactivity.[1] Decreased levels of TRPV1 and P2X3-IR have been demonstrated in submucosal biopsies obtained after intravesical injection of botulinum toxin A.[1]

Relevant Anatomy

The adult bladder is located in the anterior pelvis and is enveloped by extraperitoneal fat and connective tissue. It is separated from the pubic symphysis by an anterior prevesical space known as the retropubic space (of Retzius). The dome of the bladder is covered by peritoneum, and the bladder neck is fixed to neighboring structures by reflections of the pelvic fascia and by true ligaments of the pelvis.

The body of the bladder receives support from the external urethral sphincter muscle and the perineal membrane inferiorly and the obturator internus muscles laterally (see the image below).

Gross anatomy of the bladder. Gross anatomy of the bladder.

For more information about the relevant anatomy, see Bladder Anatomy.

Indications

Intradetrusor injection of onabotulinumtoxinA is approved by the FDA for the treatment of urinary incontinence due to detrusor overactivity associated with a neurologic condition in adults who have an inadequate response to or are intolerant of an anticholinergic medication. Clinical trials have been performed in patients with multiple sclerosis and spinal cord injury. In such individuals, botulinum toxin A was used as monotherapy or in conjunction with anticholinergic therapy. More recently, onabotulinumtoxinA has been approved for the treatment of overactive bladder in patients who are refractory to or intolerant of anticholinergic agents.

Contraindications

OnabotulinumtoxinA is contraindicated in the presence of infection at the proposed site(s) and in individuals with known hypersensitivity to any botulinum toxin preparation or to any of the components in the formulation. It is also contraindicated in patients with detrusor overactivity associated with a neurologic condition who have an acute urinary tract infection, as well as in patients with acute urinary retention who are not routinely performing clean intermittent self-catheterization (CIC).

Warnings and precautions include the following:

  • Potency units of onabotulinumtoxinA are not interchangeable with other preparations of botulinum toxin products

  • Postmarketing reports indicate that the effects of onabotulinumtoxinA and all botulinum toxin products may spread from the area of injection to produce symptoms consistent with botulinum toxin effects. These may include asthenia, generalized muscle weakness, diplopia, blurred vision, ptosis, dysphagia, dysphonia, dysarthria, urinary incontinence, and breathing difficulties

Potential drug interactions must be taken into account. Patients receiving concomitant treatment with onabotulinumtoxinA and aminoglycosides or other agents interfering with neuromuscular transmission (eg, curare-like agents) or muscle relaxants, should be observed closely because the effect of onabotulinumtoxinA may be potentiated.

Potential transmission of viral disease must also be considered. OnabotulinumtoxinA contains albumin. On the basis of effective donor screening and product manufacturing processes, onabotulinumtoxinA carries an extremely remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD) is also considered extremely remote. No cases of transmission of viral diseases or CJD have ever been reported for albumin.

Outcomes

Safety and efficacy

Kuo, in a study assessing whether suburothelial injection of different doses of botulinum toxin A would have a similar therapeutic effect to but less side effects than the use of 200 U botulinum toxin-A in patients with refractory detrusor overactivity, found that a dose of 100 U, compared with 150 or 200 U, achieved a similar rate of excellent results and had significantly fewer adverse events; the dose also affected the duration of therapeutic effectiveness.[2]

In this study, 75 patients were enrolled and randomized to receive 100, 150, or 200 U botulinum toxin-A injected suburothelially at 40 sites.[2] Of the 75, 40 had NDO. Of these 40, 22 had chronic cerebrovascular accidents or Parkinson disease and 18 a spinal cord injury or multiple sclerosis. All patients voided by reflex or abdominal stimulation and had baseline postvoid residual volumes smaller than 150 mL.

When patients with NDO were compared with those with idiopathic detrusor overactivity (IDO), the former had significantly greater rates of excellent (patient achieved continence with a voiding difficulty grade increased by less than 2) and improved (incontinence grade improved by 1 or more points compared to baseline and voiding difficulty increased by less than 2) results (97.5% versus 77.1%).

When NDO and IDO patients were considered together, cystometric bladder capacity at 1 month increased by 1.8 times, 1.73 times, and 1.56 times the baseline value for patients treated with 200, 150, and 100 U of botulinum toxin A, respectively; capacity at 3 months increased by 1.5, 1.4, and 1.3 times the baseline value.[2] Mean postvoid residual volume increased by 3-4 times the baseline value at 1 month in all treatment groups and remained significantly increased at 3 months in patients who received 150 and 200 U of botulinum toxin A.

A randomized, double-blind phase III study by Tullman et al reported that onabotulinumtoxinA significantly reduced urinary incontinence at week 6 compared to the placebo in noncatheterizing patients with multiple sclerosis. The study also reported that 53% of patients treated with onabotulinumtoxinA achieved 100% reduction of urinary incontinence comparted to 10.3% in the placebo group. Significant improvements in quality of life and lower clean intermittent catheterization rates than were previously reported were also seen.[3]

 

Schurch et al, in a double-blind, randomized, placebo-controlled, parallel-group study aimed at determining the safety and efficacy of 200 and 300 U botulinum toxin A injections into the detrusor in patients with NDO (primarily related to spinal cord injury [SCI]), found that such injections provided rapid, well-tolerated, clinically significant decreases in the signs and symptoms of urinary incontinence.[4]

In this study, 59 patients (53 with SCI and 6 with multiple sclerosis) with NDO and incontinence requiring clean intermittent catheterization were randomized to either 200 or 300 U of botulinum toxin A or to placebo.[4] Endpoints included changes in daily frequency of urinary incontinence episodes (primary endpoint), urodynamic parameters, and impact on quality of life (QoL) as determined by the Incontinence Quality of Life questionnaire.

Significant posttreatment decreases in incontinence episodes from baseline occurred in both treatment groups but not in the placebo group.[4] Significant decreases in incontinence episodes at all time points were seen in the 2 botulinum toxin A groups (except for weeks 12 and 18 in the 200 U group) but not in the placebo group. Compared with placebo, the difference between treatment groups was significantly in favor of the 300 U group at weeks 2 and 6 and the 200 U group at week 24. Anticholinergic use remained similar throughout.

The mean maximal cystometric bladder capacity increased significantly from baseline in each botulinum toxin A treatment group at all posttreatment time points, although no significant changes were noted in the placebo group.[4] Mean changes from baseline in the 2 treatment groups were significantly higher as compared with the placebo group at every time point except week 24 in the 300 U group.

The overall incidence of patients experiencing at least 1 adverse event was not significantly different among the treatment groups, and no such events were considered to be related to the study group.[4] No cases of autonomic dysreflexia were noted.

Giannantoni et al evaluated the effectiveness and safety of intravesical resiniferatoxin and botulinum toxin A injections into the detrusor muscle in a group of SCI patients with NDO unresponsive to conventional anticholinergic therapy and found that botulinum A toxin injections provided superior clinical and urodynamic benefits.[5]

In this study, 25 patients were randomly assigned to receive either resiniferatoxin 0.6 µM diluted in 30 mL of 0.9% sodium chloride or intradetrusor injections of botulinum toxin A 300 U diluted in 30 mL 0.9% sodium chloride.[5] Patients were asked to decrease the daily dosage of anticholinergics within 15 days of the beginning of treatment.

The frequency of incontinence episodes in the botulinum toxin A arm significantly decreased compared with the resiniferatoxin arm at 6, 12, and 18 months’ follow-up.[5] In addition, the uninhibited detrusor contractions threshold and the maximum bladder capacity significantly increased; the maximum pressure of uninhibited detrusor contractions in the botulinum toxin A arm significantly decreased as compared to the resiniferatoxin arm at 6, 12, and 18 months’ follow-up.

The investigators did not identify any local side effects during and after intradetrusor injections.[5] One patient experienced mild asthenia soon after the first treatment, which persisted for 10 days. Seven patients in the botulinum toxin A arm continued to take anticholinergics during follow-up, but the dosage was decreased by an average of 62.5% compared with 10 patients who continued anticholinergic therapy during the entire observation; dosage in the resiniferatoxin group decreased by an average of 56.4%.

A study by Kim et al reported that preoperative bladder compliance and open bladder neck were important predictors of outcome after botulinum toxin-A intradetrusor injection.[6]

A study by Peyronnet et al found that after failure of a first detrusor injection of botulinum toxin for neurogenic detrusor overactivity, a switch to a different toxin seems to be more effective than a second injection of the same toxin.[7]

Quality of life

Khan et al, in a prospective, open-label, single-center study evaluating the effect of repeat detrusor botulinum toxin A injections on urinary symptoms, health, and QoL in 137 patients with refractory NDO secondary to multiple sclerosis who were treated with botulinum toxin A between 2002 and 2009, found that these repeat injections resulted in sustained improvements in QoL.[8]

Of the patients in this study who underwent detrusor botulinum toxin A treatment, 99 (72%) returned for a second treatment; 47, 25, 14, and 5 returned for retreatments 3, 4, 5, and 6, respectively.[8] Impact on QoL was assessed by means of the Urogenital Distress Inventory (UDI-6), the Incontinence Impact Questionnaire (IIQ-7), and the EuroQol-5 Dimensions questionnaires before and 4 weeks after botulinum treatment.

The mean UDI-6 and IIQ-7 scores showed considerable improvement 4 weeks after each treatment, even when repeated 6 times.[8] The mean differences in UDI-6 and IIQ-7 scores were 38.2 and 46.2, respectively, for injection 1, 33.5, and 40.1 for injection 2, 38.6 and 41 for injection 3, and 33.7 and 41.6 for injection 4. Before the first injection, 65% relied on CIC; after the first treatment, 95% relied on CIC.

Kalsi et al used the short forms of UDI-6 and IIQ-7 to evaluated changes in QoL 4 and 16 weeks after treatment with intradetrusor botulinum toxin A injections (300 U for NDO and 200 U for IDO) in 48 patients (32 with NDO and 16 with IDO); they found highly significant improvements in QoL at 4 weeks, which were maintained at 16 weeks in both patient subgroups.[9]

 

Periprocedural Care

Equipment

Devices

Injection of botulinum toxin A may be performed by means of either rigid or flexible cystoscopy. Various different endoscopic needles may be used for the injection, in particular ultrafine 4-mm flexible needles that may be passed through the flexible cystoscope. Besides the 4-mm flexible needle, the needle used for collagen injection and the needle used for dextranomer or hyaluronic acid injection have also been used for this procedure.

Botulinum toxin A

OnabotulinumtoxinA (ie, BOTOX) is supplied in single-use 100-U and 200-U vials. Before injection, each vacuum-dried vial must be reconstituted (see below). After reconstitution, onabotulinumtoxinA should be administered within 24 hours. Reconstituted onabotulinumtoxinA should be stored in a refrigerator at a temperature of 2-8° C.

In treating adult patients for 1 or more indications, the maximum cumulative dose generally should not exceed 360 U in a 3-month period. The recommended treatment dose of onabotulinumtoxinA is 200 U per treatment, divided into 30 injections of 1 mL.

Options for reconstitution

Reconstitution of onabotulinumtoxinA may be accomplished in 1 of 2 ways. The first is to reconstitute a 200-U vial by adding 6 mL of 0.9% sterile nonpreserved saline solution, mixing gently, and withdrawing 2 mL from the vial into each of 3 separate 10-mL syringes. Reconstitution is completed by adding 8 mL of 0.9% nonpreserved saline solution into each of the 10-mL syringes and mixing gently. Each of the 3 syringes will then contain 10 mL (about 67 U of onabotulinumtoxinA), for a total of 200 U of reconstituted onabotulinumtoxinA.

The second option is to reconstitute a pair of 100-U vials by placing 6 mL of 0.9% nonpreserved saline solution into each one, mixing the vials gently, withdrawing 4 mL from each of the 2 vials into 2 separate 10-mL syringes, and withdrawing the remaining 2 mL from each vial into a third 10-mL syringe. Reconstitution is completed by adding 6 mL of 0.9% nonpreserved saline into each of the 10-mL syringes and mixing gently. As with the first option, each of the 3 syringes will then contain 10 mL (about 67 U of onabotulinumtoxinA), for a total dose of 200 U.

Patient Preparation

Intradetrusor injection of onabotulinumtoxinA may be performed via flexible or rigid cystoscopy and may involve either local anesthesia (with or without sedation) or general anesthesia, depending on the patient’s sensory status, anxiety level, and risk of autonomic dysreflexia. In patients who are at risk for autonomic dysreflexia or have experienced autonomic dysreflexia with previous bladder filling, consideration of monitoring or pretreatment may be indicated.

Patients undergoing injection of botulinum toxin A should not have an acute urinary tract infection. It is recommended that prophylactic antibiotics (except aminoglycosides, because of the potential for drug interactions) be administered 1-3 days before treatment, on the day of treatment, and 1-3 days after treatment.

 

Technique

Approach Consideration

Intradetrusor injection of botulinum toxin A may be performed via rigid or flexible cystoscopy, depending on the urologist’s preference and the patient’s sensory level. Before injections are initiated, the injection needle should be filled (primed) with approximately 1 mL of reconstituted onabotulinumtoxinA to remove any air (the exact volume will depend on the needle used). Sufficient saline should be instilled into the bladder to achieve adequate visualization for the injections, but overdistention should be avoided.

The needle is inserted into the detrusor muscle to a depth of approximately 2 mm. A total of 30 injections (each containing 1 mL, or approximately 67 U of botulinum toxin A), equally spaced about 1 cm apart, are made into the dome, posterior, and right and left lateral walls of the bladder; the trigone is spared (see the image below). The bladder is then emptied, and the patient is observed for at least 30 minutes after injection.

Injection sites using minimally invasive outpatien Injection sites using minimally invasive outpatient technique. Flexible cystoscope with superfine 27-gauge disposable needle is used to inject onabotulinumtoxinA (BOTOX; Allergan, Irvine, CA) into bladder while avoiding trigone. At equally spaced points, 30 distinct injections, each containing 1 mL, are introduced

Kuo described a suburothelial technique that uses a rigid cystoscope and a 23-gauge injection needle.[2] In this approach, the needle is inserted into the submucosal space, and the botulinum toxin A solution is injected to form a ballooning of the bladder mucosa.

Reinjection may be performed when the clinical effect of the previous injection decreases, but no sooner than 12 weeks after the preceding bladder injection.

Complications

In 3 randomized, controlled trials, the most common adverse event (AE) of intradetrusor injection of botulinum toxin A was increased postvoid residual, which may necessitate clean intermittent catheterization. Thus, patients should be counseled about the potential need for clean intermittent self-catheterization (CIC).

A placebo-controlled study reported that the overall incidence of least 1 AE in treated patients was not significantly different from that in the placebo group.[4] The more frequently reported AEs across the studies were urinary tract infection and mild hematuria.

A dose-ranging study including both neurogenic detrusor overactivity (NDO) and idiopathic detrusor overactivity (IDO) patients reported that patients who received 100 U of botulinum toxin A had a significantly smaller postvoid residual urine volume than patients who received 150 U or 100 U at 1 month.[2] One study reported a mild case of asthenia after injection of botulinum toxin A 300 U, which persisted for 10 days.[5]

 

Medication

Neuromuscular Blockers, Botulinum Toxins

Class Summary

Agents in this class cause presynaptic paralysis of the myoneural junction and reduce abnormal contractions.

Onabotulinumtoxin A (BOTOX)

Botulinum toxin may provide relief of spasticity without the systemic adverse effects of other antispasticity agents. Binds to receptor sites on the motor nerve terminals and, after uptake, inhibits the release of acetylcholine, blocking transmission of impulses in neuromuscular tissue.

In treating adult patients for 1 or more indications, the maximum cumulative dose generally should not exceed 360 U in a 3-month period. The recommended treatment dose of onabotulinumtoxin A is 200 U per treatment, divided into 30 injections of 1 mL.

 

Questions & Answers

Overview

What are botulinum toxin injections to treat neurogenic detrusor overactivity?

What is the bladder anatomy relevant to botulinum toxin injections to treat neurogenic detrusor overactivity?

What are the FDA approved uses of onabotulinumtoxinA (BOTOX) injections to treat bladder overactivity?

When are botulinum toxin injections contraindicated for the treatment of neurogenic detrusor overactivity?

What is the efficacy and safety of botulinum toxin injections to treat neurogenic detrusor overactivity?

What is the effect on quality of life of botulinum toxin injections to treat neurogenic detrusor overactivity?

Periprocedural Care

What equipment is needed to administer botulinum toxin injections to treat neurogenic detrusor overactivity?

How is onabotulinumtoxinA (BOTOX) supplied for injections to treat neurogenic detrusor overactivity?

What is the dosage and frequency of botulinum toxin injections to treat neurogenic detrusor overactivity?

How is onabotulinumtoxinA (BOTOX) reconstituted for injections to treat neurogenic detrusor overactivity?

How are patients prepped for botulinum toxin injections to treat neurogenic detrusor overactivity?

Technique

How are botulinum toxin injections administered to treat neurogenic detrusor overactivity?

What are the possible adverse effects of botulinum toxin injections to treat neurogenic detrusor overactivity?

Medications

Which medications in the drug class Neuromuscular Blockers, Botulinum Toxins are used in the treatment of Botulinum Toxin Injections for Neurogenic Detrusor Overactivity?