Correspondence *Guy's and St Thomas' Hospitals, Department of Urology, St Thomas Street, London SE1 9RT, UK

Email prokarurol@gmail.com

The case

A 49-year old man presented with a 17-year history of detrusor overactivity secondary to transverse myelitis, for which he underwent clam ileocystoplasty 14 years ago. He then needed a revision of the original procedure 3 years later. Both procedures provided symptomatic relief that lasted only 6 months. The patient continued to experience significant lower urinary tract symptoms (LUTS) and, when referred to our department, usually had to wear a penile sheath despite his use of clean intermittent self-catheterization (CISC) and oral anticholinergic agents.

His initial evaluation on presentation to our department included a 4-day bladder diary that assessed voiding frequency (mean number of CISCs in 24 h), urgency (mean number of CISCs associated with urgency in 24 h), and incontinence (mean number of urge incontinence episodes in 24 h). Standard subtraction cystometry was also performed after discontinuation of anticholinergic drugs for 10 days, to look for evidence of detrusor overactivity and determine the maximum cystometric capacity (MCC) and maximum detrusor pressure during bladder filling (Pdet_max). The effect of the patient's condition on his quality of life (QOL) was measured using the short forms of the Urogenital Distress Inventory and Incontinence Impact Questionnaire.

The bladder diary confirmed the presence of significant LUTS (Table 1), which were attributed to terminal detrusor overactivity as demonstrated by the patient's cystometry findings (Figure 1A). Cystometry also showed a decrease in MCC and an increase in Pdet_max (Table 1). The patient was distressed by his frequency and urge incontinence (as shown by a maximum score in Urogenital Distress Inventory questions 1 and 2), which had had a large effect on his physical and social activities (as shown by maximum scores in Incontinence Impact Questionnaire questions 2–5).¹

Figure 1 Changes in subtraction cystometry after treatment with BTX-A injections

(A) Terminal detrusor overactivity at reduced cystometric capacity was present before BTX-A treatment. (B) Restoration of maximum cystometric capacity to normal levels, and an improvement in filling detrusor pressure trace had occurred by 4 weeks post-treatment. (C) A further improvement, with almost complete abolition of detrusor overactivity, was noted at 16 weeks post-treatment. Note that the detrusor pressure values recorded here correspond to the end filling pressures, not to the maximum detrusor pressure. Abbreviations: P_abd (red), intra-abdominal pressure (cmH₂O); P_det (purple), detrusor pressure (cmH₂O); P_ves (light blue), intravesical pressure (cmH₂O); Q_ura (yellow), flow rate of voiding; V_infus (green), infused volume; V_ura (dark blue), volume of voided urine.

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Table 1 Changes in lower urinary tract symptoms, urodynamic parameters and quality-of-life score after treatment with botulinum A toxin

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After consultation and discussion about the possible major complications such as generalized muscle weakness, paralysis and the probable need for intensive care unit admission, the patient consented to treatment with intradetrusor injections of botulinum toxin A (BTX-A). After oral antibiotic prophylaxis (ciprofloxacin 500 mg, started immediately), 20 ml of 2% lignocaine gel was instilled into the patient's urethra. The bladder was accessed using a flexible cystoscope (CYF-4, Olympus Keymed, Milton Keynes, UK) that accommodates a flexible injection needle with a working length of 1,050 mm and a needle length of 4 mm (MAJ-656, Olympus Keymed). A total of 200 U of BTX-A (BOTOX^® Allergan Ltd, UK) diluted in 20 ml of normal saline was injected via the cystoscope under local anesthesia, at 20 different sites into the bladder wall (sparing the trigone) as previously described,² and at least 1 cm away from the bowel–bladder anastomosis. The procedure was completed in 30 min. The patient graded his discomfort from these injections at 3 on the verbal 11-point Box Scale.³

The patient was discharged fit and well after a 24 h observation period, and given a 5-day course of prophylactic antibiotics (ciprofloxacin 500 mg twice daily). He was assessed 4 and 16 weeks after the procedure, with cystometry, a bladder diary, QOL questionnaires and cystoscopy, as at baseline. At 4 weeks, improvements were noted in all LUTS and in the QOL scores, which had improved further at 16 weeks (Table 1). The patient was completely dry on CISC only at both follow-up visits, and did not require anticholinergic drugs or the use of a penile sheath. Urodynamic parameters showed progressive amelioration, with normalization of both MCC and Pdet_max at 16 weeks (Table 1 and Figure 1A–1C), with an almost complete abolition of evidence of detrusor overactivity (Figure 1C). Both follow-up cystoscopies were unremarkable. There were no side effects of BTX-A treatment.

The patient reported a partial return of his LUTS 11 months after BTX-A treatment, which to date (currently 2 years after BTX-A treatment) have been successfully controlled with the addition of oral anticholinergic drugs. His neurological condition remains unchanged since pre-BTX-A screening.

Discussion of diagnosis

Overactive bladder syndrome (OABS) is a common condition with a socioeconomic impact comparable to that of diabetes.⁴ The clinical features of bladder dysfunction in patients with OABS include urgency and frequency, with or without urge incontinence. The most common etiology of OABS is detrusor overactivity of either neurogenic or idiopathic origin. The diagnosis of detrusor overactivity is made by urodynamic assessment, and standard cystometry is the most commonly applied test to differentiate between OABS caused by detrusor overactivity and urgency-frequency syndrome caused by increased bladder sensation, since the two conditions share common symptoms.⁵ The results of concomitant electromyography during cystometrography have little influence on treatment decision-making in the management of patients with neurogenic detrusor overactivity, and other special tests (such as the ice-water test) lack credible specificity and sensitivity. These investigations have, therefore, been rendered optional and complementary to conventional urodynamic assessment.⁶ A reduced filling rate is now applied during cystometry in patients with detrusor overactivity independent of aetiology (NDO or IDO) to avoid a biased measurement of urodynamic parameters.⁶ Research into the pathophysiology of neurogenic detrusor overactivity of spinal origin has suggested that the emergence of an aberrant segmental sacral spinal reflex mediated by vanilloid-sensitive, C-fiber afferent nerves contributes to detrusor overactivity.⁷ Such findings have become the basis for application of experimental treatments that aim to improve symptoms of detrusor overactivity by modulation of bladder afferent pathways.

Treatment and management

Oral pharmacotherapy, alone or combined with CISC, allows for adequate symptomatic control in the majority of patients with neurogenic lower urinary tract dysfunction, while protecting the upper urinary tract and minimizing the incidence of urinary tract infections.⁸ Oral antimuscarinic agents have a documented suppressive effect on incontinence associated with detrusor overactivity.⁶ Despite their good efficacy rate (approximately 70%), their long-term use can be limited by side effects related to their systemic effects on antimuscarinic cholinergic receptors. Over the past 5 years, controlled studies of antimuscarinic agents have revealed a large placebo effect (up to 40% of patients) in controlled studies of antimuscarinic agents. Some researchers have recently proposed that antimuscarinic drugs exert their effects during the bladder storage phase, via suppression of the release of acetylcholine from the urothelium and suburothelial nerves during progressive bladder distension.⁹ Preclinical data have confirmed an effect of antimuscarinic agents on C-fiber bladder afferent nerves.

Augmentation cystoplasty was introduced over 20 years ago as a treatment for patients with detrusor overactivity that is refractory to conservative management with antimuscarinic drugs. Augmentation cystoplasty remains largely the treatment of choice for such patients, with efficacy rates approaching 90% in patients with neurogenic detrusor overactivity.⁸ This procedure increases bladder capacity and reduces storage pressure, but patients subsequently require regular CISC for effective bladder emptying. Augmentation cystoplasty is, moreover, a highly invasive procedure that can be associated with early complications that require reoperation, such as wound infection, bleeding, and adhesions that lead to small-bowel obstruction. Long-term adverse events of this procedure include metabolic acidosis, spontaneous bladder perforation, mucus production in the bladder, formation of urinary tract stones, need for CISC, and development of anastomotic carcinoma.⁸ Moreover, augmentation cystoplasty fails to resolve troublesome LUTS in around 8% (mean value) of treated patients with neurogenic detrusor overactivity.⁸ In this patient, despite the use of oral medication, CISC and continence aids, his bothersome symptoms were only partially controlled.

Intravesical therapies, such as the vanilloids, capsaicin and resiniferatoxin, have shown high efficacy rates (up to 84% for capsaicin, 92% for resiniferatoxin) in open-label studies.^{10, 11} These treatments have a reversible desensitizing effect on afferent nerves in the neurogenic bladder,^{12, 13} and had been proposed as an intermediate option to fill the therapeutic gap between oral medication and bladder surgery. Despite the sound scientific basis for the use of these therapies, clinical issues have minimized the potential of such compounds to be widely used in practice—in particular, poor tolerability of capsaicin instillates, which has recently been recognized to be caused by its alcohol-based solvent, and adhesion of resiniferatoxin to the administration system, together with the lack of adequate data from placebo-controlled studies.

Sacral neuromodulation is being increasingly recognized as an effective second-line treatment for the management of detrusor overactivity in patients whose condition is refractory to conservative therapies. This treatment is more suitable for patients with idiopathic bladder dysfunction or those with stable spinal cord injuries, however, than for those with progressive neurological disease. Possible mechanisms of action include activation of afferent fibers that inhibit spinal and supraspinal efferent pathways, or activation of urethral efferent nerves that cause reflex detrusor relaxation.⁶ Advances in techniques of implanting the stimulator and in the implant technology have considerably improved the surgical aspects of this therapy, but sacral neuromodulation still remains an invasive and costly option for management of these patients, and is associated with a high complication rate.

Following the introduction of BTX-A injections for the treatment of intractable detrusor overactivity in patients with spinal cord injuries, its applications have expanded to encompass various etiologies of neurogenic detrusor overactivity.^{2, 14} Significant post-treatment improvements in frequency, urgency and urge incontinence have been reported, which may enable patients to completely discontinue oral anticholinergic agents or to considerably reduce their dosage.^{2, 14} The beneficial effects of BTX-A treatment on patients' LUTS last an average of 9–11 months^{14, 15} and can be restored with repeat injections.¹⁵ Intradetrusor BTX-A injection has been found to achieve the same targets as augmentation cystoplasty in patients with neurogenic detrusor overactivity because the injections improve bladder capacity and compliance, which allow storage and elimination of urine under low pressures.^{2, 14, 16} A cascade mechanism of peripheral and central desensitization of bladder afferent pathways has been proposed as the main mode of action of BTX-A in the alleviation of detrusor overactivity and its symptoms in treated patients,¹⁷ although a synergistic and direct effect on the motor innervation of the bladder is probably important too. Side-effects include flu-like symptoms immediately after the injections and urinary tract infections, while transient generalized muscle weakness caused by systemic absorption of BTX-A has been reported in eight patients to date.¹⁸ The most common adverse effect of intradetrusor BTX-A injections is the need to perform CISC owing to incomplete bladder emptying, secondary to drug-induced changes in detrusor function.²

To our knowledge, this article describes the first use of intradetrusor BTX-A treatment in a patient in whom augmentation cystoplasty had failed to control his symptoms. In patients with spinal cord lesions and severe detrusor overactivity, bladder contractions might not be completely abolished after augmentation cystoplasty. The most probable etiology of ongoing LUTS after augmentation cystoplasty is a persistent, contracted anastomosis of enterocystoplasty. After surgical injury of the bladder, repetitive detrusor contractions may occur that induce contracture of the anastomosis of enterocystoplasty. A narrowed anastomosis may prohibit pressure transmission to the augmented part of the bladder, and result in high intravesical pressures and persistent urinary incontinence during reflex detrusor contractions. Prevention of bladder contractions that occur immediately after enterocystoplasty by intraoperative injections of BTX-A into the detrusor might be an effective way to facilitate formation of a wide anastomosis.

For this patient, an obvious concern was the possible development of generalized muscle weakness¹⁸ or even botulism through systemic absorption of BTX-A via the enteric circulation. To minimize this risk, we used 200 U of BTX-A instead of the 300 U dose that is widely used for neurogenic detrusor overactivity,^{14, 15} and caution was taken to avoid injection of the bowel patch. The treatment was well tolerated under local anesthesia and the symptomatic response was dramatic, with normalization of bladder capacity and detrusor pressures. These improvements were also reflected in the patient's improved QOL score.

Conclusion

Intradetrusor injections of BTX-A produced a significant amelioration of this patient's otherwise intractable symptoms of neurogenic detrusor overactivity, despite the fact that he had twice previously undergone reconstructive surgery of the lower urinary tract. In selected patients, intradetrusor BTX-A injections could provide a salvage treatment option after an augmentation cystoplasty fails to improve LUTS. Caution should be exercised with regard to possible systemic side effects.

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Subject areas under which this article appears: Urinary incontinence, urodynamics and lower urinary tract dysfunction