Urologic applications of botulinum toxin

TREATMENT OF IDIOPATHIC OVERACTIVE BLADDER

Patients with idiopathic overactive bladder have urinary urgency accompanied by urgency incontinence, nocturia, or urinary frequency.¹⁸ The prevalence of this condition has been reported to range from 1.7% to 13.3% in men age 30 and older and 7% to 30.3% in women of similar ages. About one-third of women with overactive bladder also have detrusor overactivity.¹⁹ Overactive bladder presents a significant economic and medical burden on the healthcare system, as well as having a negative impact on quality of life.

The FDA approved botulinum toxin injection for treatment of idiopathic overactive bladder in January 2013.

Evidence of effectiveness

Two multicenter randomized controlled trials^20,21 of botulinum toxin 100 U enrolled patients age 18 and older who had more than three episodes of urinary urgency incontinence in a 3-day period or more than eight micturitions per day inadequately managed by anticholinergic drug therapy. Primary end points were the change from baseline in the number of episodes of urinary incontinence per day and the proportion of patients with a positive response on the Treatment Benefit Scale²² at week 12. Secondary end points included episodes of urinary urgency incontinence, micturition, urgency, and nocturia, and scores on health-related quality of life questionnaires (Incontinence Quality of Life scale, King’s Health Questionnaire).

In both studies, patients receiving botulinum toxin had significantly fewer episodes of incontinence compared with placebo (−2.65 vs −0.87; P < .001 and −2.95 vs −1.03; P < .001).^20,21 Reductions from baseline in all other symptoms of overactive bladder, a positive treatment response on the treatment benefit scale, and improvements in quality-of-life scores were also significantly greater with botulinum toxin injection than with placebo (P ≤ .01).

As in the studies of neurogenic detrusor overactivity, the most common adverse effects were urinary tract infection (occurring in 15.5%²⁰ and 24.1%²¹ of patients) and urinary retention requiring self-catheterization (5.4%²⁰ and 6.9%²¹).

The largest study to date of anticholinergic therapy vs botulinum toxin injection²³ in women with urinary urgency incontinence, published in 2012, studied nearly 250 women who had five or more episodes of idiopathic urgency incontinence in a 3-day period. They were randomized either to daily oral therapy (solifenacin 5 mg with possible escalation to 10 mg and, if necessary, a subsequent switch to extended-release trospium 60 mg) plus one intradetrusor injection of saline, or to a daily oral placebo plus one injection of botulinum toxin 100 U.²³

The dropout rate was low in both groups, with 93% of patients in both groups completing the 6-month protocol. Women experienced a mean reduction in urgency incontinence episodes of 3.4 per day (baseline 5) in the anticholinergic group vs 3.3 episodes in the botulinum toxin group (P = .81). However, more patients achieved complete resolution of urinary urgency incontinence in the botulinum toxin group than in the anticholinergic therapy group (27% vs 13%; P = .003). Quality of life improved in both groups without a significant difference between the groups. The botulinum toxin group had higher rates of initiation of self-catheterization (5% vs 0%, P = .01) and urinary tract infection (33% vs 13%, P < .001).²³

Botulinum toxin as a third-line therapy

In May 2014, the American Urological Association updated its guidelines on idiopathic overactive bladder²⁴ to include botulinum toxin injection as standard third-line therapy for patients in whom behavioral and medical management (ie, anticholinergics and beta-3-agonists) failed.

Interpreting the evidence to date

Overall, studies in idiopathic overactive bladder have shown a reduction in episodes of urgency incontinence and other symptoms, with some data also demonstrating a corresponding improvement in quality of life.

As in neurogenic detrusor overactivity, the main risks associated with botulinum toxin injection are urinary tract infection and the need to initiate self-catheterization. Although 94% of patients studied did not require self-catheterization after injection, the patient’s ability to perform self-catheterization should be determined before proceeding with botulinum toxin injections.

DETRUSOR EXTERNAL SPHINCTER DYSSYNERGIA

Botulinum toxin has been used not only to improve bladder storage but also to facilitate bladder emptying, as in patients with DESD, a lack of coordination between the bladder and the urinary sphincter. Normal voiding involves relaxation of the urinary sphincter and contraction of the bladder; in DESD the sphincter contracts and works against the bladder’s ability to empty. This leads not only to difficulty emptying the bladder but also to elevated bladder pressure, which can cause renal damage if untreated.

DESD can be seen after injury between the pontine micturition center, which coordinates activity between the bladder and the sphincter, and the caudal spinal cord. This can occur in spinal cord injury, multiple sclerosis, myelomeningocele, and transverse myelitis and can cause significant morbidity for the patient.

Treatment options include drug therapy, injection of botulinum toxin into the sphincter, clean intermittent catheterization, indwelling catheterization, urethral stenting, sphincterotomy, and reconstructive surgery such as urinary diversion.²⁵

The goals of therapy are to avoid the need for clean intermittent catheterization in patients who have difficulty with manual dexterity, and to avoid the need for surgical procedures such as sphincterotomy and urinary diversion. The efficacy of urethral stenting is low, and medical management can be limited.²⁶

DESD leads to difficulty emptying the bladder, elevated bladder pressure, and, if untreated, renal damage

In the first published report on botulinum toxin for DESD (in 1988),²⁷ of 11 patients with spinal cord injury and DESD who received botulinum toxin injected into the external urethral sphincter, 10 showed signs of sphincter denervation on electromyography and reductions in urethral pressure profiles and postvoid residual volumes. Schurch et al²⁸ and de Sèze et al²⁹ also reported reductions in postvoid residual volume and maximal urethral pressures in patients with spinal cord injury and DESD.

In 2005, Gallien et al³⁰ reported what is still the largest multicenter randomized controlled trial of botulinum toxin injection in DESD. Eighty-six patients with multiple sclerosis, DESD, and chronic urinary retention were randomized to receive either a single transperineal botulinum toxin injection of 100 U plus the alpha-1-blocker alfuzosin, or a placebo injection plus alfuzosin. Botulinum toxin treatment was associated with significantly increased voided volumes and reduced premicturition and maximal detrusor pressures, but no significant decrease in postvoid residual volume.³⁰

More study needed

Despite these findings, a Cochrane Review concluded that, given the limited experience with intrasphincteric injection of botulinum toxin, data from larger randomized controlled trials are needed before making definitive recommendations.²⁵ In the meantime, the clinician must weigh the low morbidity of the procedure against the limited options in the treatment of these patients.