original article The Successful and Novel Treatment of Non-Neurogenic - External Sphincter Dyssynergia (DESD) with Botulinum Toxin A Tricia LC Kuo, MBBS, MRCSEd, M Med (Surg), FAMS, Lay Guat Ng, MBBS, FRCS (Edin), M Med(Surg), FAMS Department of Urology, Urology Centre, Singapore General Hospital Abstract Introduction: Our study aims to examine the treatment outcomes of patients with non-neurogenic detrusorexternal sphincter dyssynergia (DESD) after the injection of botulinum toxin A (BTX-A, Botox ) to the external sphincter. Methods: A retrospective review of nine patients with DESD was performed. All patients were diagnosed with the aid of video urodynamic studies. Pre-operative evaluation was standardised using bladder diary, urine microscopy and culture, bedside ultrasound of the kidneys and bladder, and renal function test. Each received BTX-A injection of 50 100U to the external sphincter. The pre-operative and post-operative maximum flow rate (Qmax) and post-void residual urine (PVRU) were objectively compared using paired-samples t test. Results: All the injections were performed from December 2006 to March 2008. Of the nine patients, seven (77.8%) were female and two (22.2%) were male. The mean age was 49.2 years (range 20 64 years). The mean pre-operative maximum flow rate (Qmax) was 9.7±6.26 ml/s. A month later, the post-operative Qmax improved to 16.5±11.3 ml/s. Mean difference in Qmax was 6.76±8.1 ml/s (P = 0.037). The mean preoperative post void residual urine (PVRU) was 179.2±86.8 ml. This improved to 45.7±44.4 ml post-operatively. The mean difference in PVRU of 133.6±77.2 ml (P = 0.001). Conclusion: In patients with DESD, there is a significant improvement in PVRU and Qmax after the injection of BTX-A. Hence, BTX-A injection is an effective method of treatment for DESD. However, further studies and followup are required to further evaluate patient satisfaction, quality of life and need for repeated injections. Keywords: Botulinum toxin, -sphincter dyssynergia, Non-neurogenic detrusor dysfunction INTRODUCTION Botulinum toxin A (BTX-A, Botox ) was first introduced in Urology by Dykstra 1 in 1988 for the treatment of detrusor sphincter dyssynergia in patients with spinal cord injury. Subsequent studies of sphincter spasticity in adult patients had significant positive results, especially decreased PVRU 2-7. The use of BTX-A in children has been further examined, including children with nonneurogenic neurogenic bladder dysfunction, with good outcomes 8-9. Non-neurogenic functional bladder outlet obstruction (in the absence of anatomical abnormality) can arise from sphincter dyssynergia. These may also be termed non-neurogenic neurogenic bladder, Hinman syndrome or external sphincter pseudodyssynergia. Essentially in DESD, there is urodynamic evidence of bladder outlet obstruction, secondary to a kinesiologic disassociation of the two groups of muscles that generally work in harmony (the detrusor and the external sphincter), in the absence of any neurological abnormalities. High voiding s secondary to bladder outlet obstruction can lead to long-term renal damage. As such, traditional treatment modalities for DESD typically aim to reduce voiding s. These options include urethral stents, balloon dilatation Proceedings of Singapore Healthcare Volume 22 Number 2 2013 93
Original Article Fig. 1. Urodynamic study involuntary contractions of the external urethral sphincter, resulting in high intravesical s during the voiding phase. and external sphincterotomy. Our study aims to show that adult patients with DESD can be treated successfully with the injection of BTX-A to the external sphincter, negating the need for drastic surgical measures. METHODS From December 2006 to March 2008, a total of nine patients were found to have DESD and treated. The treatment records of these patients were reviewed retrospectively. All patients were diagnosed with DESD with the aid of video urodynamic studies (UDS). DESD was recognised by the involuntary contractions of the external urethral sphincter during a detrusor contraction (Fig. 1). The micturating cystogram showed ballooning of proximal urethra, associated with external sphincter pinching (Fig. 2). The dilatation of the proximal urethra in male patients confirmed that the level of obstruction was distal to the level of the prostatic urethra. procedure conducted under GA, with the external sphincter identified under direct vision using a rigid cystoscope. Injections were done at four points, namely the 3, 6, 9 and 12 o clock position, with 25U (diluted to 1ml) of BTX-A at each point. Female patients had the procedure under LA, with the injection done using an insulin syringe at the 3 and 9 o clock position, with 25-50U (diluted to 1 ml). The procedure was done as a day surgery procedure. All patients recovered well and were discharged on the same day. Post-operatively, these patients were assessed at the clinic four to six weeks later using uroflowmetry and bedside ultrasonography. The pre-operative and post-operative Qmax and PVRU were objectively compared using paired-samples t test (SPSS 16.0). A P <0.05 was considered to be statistically significant. Pre-operative evaluation was similar in all patients and standardised. Patients kept a bladder diary, had a bedside ultrasound of the kidneys and bladder, and a renal function test. Urine microscopy and culture was done in all cases to exclude urinary tract infection. Each patient received BTX-A (OnabotulinumtoxinA) injection of 50-100U, diluted with normal saline, to the external sphincter under local (LA) or general anaesthesia (GA). Male patients had the Fig. 2. Ballooning of proximal urethra, associated with external sphincter pinching 94
Botulinum Toxin on DESD Table 1. Patient Characteristics and Clinical Presentation. Patient Sex Age (years) Symptoms Botulinum toxin dose (units) 1 F 53 Poor stream, dysuria 50 2 F 56 Dysuria, frequency, urgency, nocturia 50 3 F 46 Acute retention of urine (ARU), urgency, pain 100 4 F 64 Urinary incontinence, pain 50 5 F 43 Hesitancy, pain 50 6 M 20 ARU, hesitancy 50 7 M 56 Weak stream, incomplete voiding 100 8 F 51 Dysuria 50 9 F 54 Weak stream 100 RESULTS All the injections were performed from December 2006 to March 2008. Of the nine patients, seven (77.8%) were female and two (22.2%) were male. The mean age was 49.2 years (range 20-64 years). Patient characteristics including presenting complaints are shown in Table 1. The mean pre-operative Qmax was 9.7±6.26 ml/s. This improved to 16.5±11.3 ml/s post-operatively. The mean difference in Qmax was 6.76±8.1 ml/s (P=0.037). There is a significant improvement in the pre-operative Qmax compared to the post-operative Qmax (Fig. 3). An uroflow trace demonstrates the dramatic improvement six weeks after treatment (Fig. 4). Similarly, we compared the PVRU before and after treatment. The mean preoperative PVRU was 179.2±86.8 ml. This improved to 45.7±44.4 ml post-operatively. The mean difference in PVRU was 133.6±77.2 ml (P=0.001). The difference is also statistically significant (Fig. 5). A summary all urodynamic findings is as shown in Table 2. At subsequent follow-up, four out of nine patients (44.4%) required repeated injections of BTX-A into the external sphincter. The mean time interval between the first and second injection was 9.5 months (range 4 14 months), and the time interval between the second and third injection was 11 months (range 2 23 months). None of the patients suffered from adverse events, for example, stress incontinence, urinary tract infections or bleeding post-operatively. DISCUSSION In today s urologic practice, BTX-A is widely established as part of the armamentarium for the treatment of refractory detrusor overactivity (DO). A multi-centre trial involving 10 European centres, showed an improvement in continence and quality of life after treatment 10. Local experience in managing neurogenic DO in patients with spinal cord injury with injection of BTX-A has also shown good results. There were improvements in continence, bladder capacity, decreased maximal detrusor s and better patient satisfaction 11. At our institution, we previously evaluated the use of BTX-A as a treatment of idiopathic detrusor over-activity for 19 patients with symptoms of overactive bladder. Our prospective study showed improvement in both subjective and objective measurements posttreatment 12. Fig. 3. Changes in Qmax after injection of BTX-A The mechanism of action of BTX-A is through the inhibition of signal transmission at the neuromuscular junction. Botulinum toxin is 95
Original Article Before Injection After Injection Fig. 4. Uroflow of a patient before and after treatment with BTX-A Treatment is needed to prevent recurrent urinary tract infections and upper tract complications, particularly if the patient has high detrusor leak point s (DLPP) 15. However, the use of BTX-A for the treatment of non-neurogenic DESD in adult patients is not common. Fig. 5. Changes in PVRU after injection of BTX-A produced by the bacteria Clostridium botulinum. There are four genetically distinct groups of the anaerobe that produce seven different immunogenic toxins, labelled A to G. The active, dichain polypeptide form of botulinum toxin consists of a heavy chain (~100 kda) connected by a disulfide bond to a light chain (~50kDa) with an associated zinc (Zn) atom. BTX-A cleaves synaptosomal-associated protein (SNAP-25), which prevents exocytosis of neurotransmittercontaining vesicles at the nerve terminal 13,14. Neurogenic DESD typically occur in patients with neurological pathology, for example, spinal cord lesions secondary to spinal cord injury, multiple sclerosis or transverse myelitis. Patients may have elevated intravesical s and PVRU. Non-neurogenic DESD or Hinman syndrome was first described by Hinman in 1971. He described the non-neurogenic bladder in 14 boys aged eight years old, who had incontinence, infections and obstructive uropathy 16. Current treatment consists of a combination of antibiotics, anticholinergics, alpha-blockers and bladder training. Clean intermittent self catherisation (CISC) may be required if patients have high PVRU. Steinhardt et al were the first to describe the treatment of external sphincter dyssynergia using botulinum toxin for neurologically normal children 17. This method of treatment was successfully repeated at several other centers in paediatric patients 18,19. Our study aims to study the efficacy of use of botulinum toxin in adult patients. Video urodynamic studies are used to confirm the diagnosis of non-neurogenic DESD. We have elected to conduct this examination without the use of electromyography (EMG) unlike other centres. 96
Botulinum Toxin on DESD Table 2. Urodynamic characteristics Patient Pre-operative urodynamic results Post-operative urodynamic results Compliance and presence of a stable bladder Voided volume at opening at Qmax Qmax (mls/s) PVRU Compliance and presence of a stable bladder Voided volume at opening at Qmax Qmax (mls/s) PVRU 1 Normal 61 160 120 6.4 300 Normal 150 80 80 19.4 50 2 Normal 199 150 135 8.9 35 NA 178 NA NA 11 0 3 Normal 128 146 111 6.3 158 NA 242 NA NA 23 27 4 Normal 470 24 25 24.1 210 NA 350 NA NA 43.2 50 5 Normal 70 49 38 6.7 150 NA 150 NA NA 14.6 0 6 Normal 426 260 229 12.3 300 Normal 372 222 191 11.9 130 7 Abnormal 281 112 108 7.4 150 NA 324 NA NA 10 74 8 Normal 311 62 74 12.9 100 NA 250 NA NA 7.8 80 9 Normal 221 116 110 2.5 210 NA 180 NA NA 7.4 0 We have found that this approach is less invasive as it eliminates the need for needle electrodes. Surface EMG probes have the disadvantage of being inaccurate due to patient movement. In addition, the fluoroscopic method allows diagnosis of the level of obstruction, thereby allowing the exclusion of bladder outlet obstruction secondary to prostatic enlargement in our male patients. Our results have shown a statistical difference in pre-treatment and post-treatment variables with increase in Qmax, and reduction in PVRU. This shows that BTX-A injection is a feasible form of treatment for non-neurogenic DESD. However, treatment effect may be short-lived in some patients, with some requiring repeated injections (44.4%). This and the incurred cost seem to be the main disadvantage of repeated BTX-A injections. It is observed that in our series, that the time interval between the second and third injection (mean 11 months), is longer than the time interval for the first and second (mean 9.5 months). We also acknowledge the limitations of our study including the small sample size, and the retrospective nature of the study design. Ideally there should be a validated questionnaire evaluating the patient s symptoms pre-procedure and post-procedure. Lately, there has been some concern with regards to the repeated, long-term use of BTX-A intradetrusor injections in patients with neurogenic bladder dysfunction. It is suggested that BTX-A may lead to impaired detrusor contraction strength, which could influence future treatment options 20. Therefore, long-term follow-up is required for this group of patients to ensure that there are no adverse effects or sequelae of repeated injections. CONCLUSION We have successfully demonstrated an objective improvement in Qmax and reduction in PVRU in patients with non-neurogenic DESD after the injection of BTX-A. However, further studies are required to further evaluate subjective patient satisfaction and quality of life. Long-term followup for such patients is also essential as they may require repeat injections. REFERENCES 1. Dykstra DD, Sidi AA, Scott AB, Pagel JM, Goldish GD. Effects of botulinum A toxin on detrusor-sphincter dyssynergia in spinal cord injury patients. J Urol 1988;139:919. 2. Dykstra DD, Sidi AA. Treatment of detrusor-sphincter dyssynergia with botulinum A toxin: a double blind study. Arch Phys Med Rehabil 1990;71:24. 3. Schurch B, Hodler J, Rodie B. Botulinum A toxin as a treatment of detrusor-sphincter dyssynergia in patients with spinal cord injury: MRI controlled transperineal injections. J Neurol Neurosurg Psychiatry 1997;63:474. 4. Petit H, Wiart E, Gaujard E, Le Breton F, Ferriere JM, Lagueny A et al. Botulinum A toxin treatment for detrusor sphincter dyssynergia in spinal cord disease. Spinal Cord 1998;36:91. 5. de Seze M, Petit H, Gallien P, de Seze MP, Joseph PA, Mazaux JM et al. Botulinum A toxin and detrusor sphincter dyssynergia: a double-blind lidocaine-controlled study in 13 patients with spinal cord disease. Eur Urol 2002;42:56. 97
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