Apostolos Apostolidis

Recommendations on the Use of Botulinum Toxin in the Treatment of Lower Urinary Tract Disorders and Pelvic Floor Dysfunctions: A European Consensus Report

CONTEXT The increasing body of evidence and number of potential indications for the use of botulinum neurotoxins (BoNTs) in the lower urinary tract (LUT) underlines the pressing need for evidence-based guidelines. OBJECTIVE A European expert panel consensus conference was convened with the main aim of evaluating the evidence and clinical considerations for the use of BoNTs in the treatment of urologic and pelvic-floor disorders and to propose relevant recommendations. EVIDENCE ACQUISITION The quality of evidence from fully published English-language literature in the PubMed and EMBASE databases was assessed using the European Association of Urology (EAU) levels of evidence (LoE). Recommendations were graded and approved by a unanimous consensus of the panel. EVIDENCE SYNTHESIS The use of botulinum neurotoxin type A (BoNTA) is recommended in the treatment of intractable symptoms of neurogenic detrusor overactivity (NDO) or idiopathic detrusor overactivity (IDO) in adults (grade A). Caution is recommended in IDO because the risk of voiding difficulty and duration of effect have not yet been accurately evaluated. Repeated treatment can be recommended in NDO (grade B). The depth and location for bladder injections should be within the detrusor muscle outside the trigone (grade C). Dosage in children should be determined by body weight, with caution regarding total dose if also being used for treatment of spasticity, and minimum age (grade B). Existing evidence is inconclusive for recommendations in neurogenic detrusor-sphincter dyssynergia, bladder pain syndrome, prostate diseases, and pelvic-floor disorders. The use of BoNTA in the LUT with the current dosages and techniques is considered to be safe overall (grade A). CONCLUSIONS The consensus committee recommends larger placebo-controlled and comparative trials to evaluate the efficacy of single and repeat injections, the duration of effect, the optimal dosage and injection technique, the timing for repeat injection, and the short- and long-term safety of the treatment in LUT and pelvic-floor disorders.

Parallel changes in bladder suburothelial vanilloid receptor TRPV1 and pan‐neuronal marker PGP9.5 immunoreactivity in patients with neurogenic detrusor overactivity after intravesical resiniferatoxin treatment

To compare PGP9.5 and transient receptor potential vanilloid receptor (TRPV1) suburothelial immunoreactivity between controls and patients with spinal neurogenic detrusor overactivity (NDO) before and after treatment with intravesical resiniferatoxin, as suburothelial PGP9.5‐staining nerve fibres decrease in patients with spinal NDO who respond to intravesical capsaicin, and TRPV1 is present on these suburothelial nerve fibres in normal and overactive human urinary bladder.

Contemporary Management of Lower Urinary Tract Disease With Botulinum Toxin A: A Systematic Review of Botox (OnabotulinumtoxinA) and Dysport (AbobotulinumtoxinA)

CONTEXT The use of botulinum toxin A (BoNTA) in the treatment of lower urinary tract dysfunction has expanded in recent years and the off-licence usage list includes neurogenic detrusor overactivity (NDO), idiopathic detrusor overactivity (IDO), painful bladder syndrome (PBS), and lower urinary tract symptoms resulting from bladder outflow obstruction (BOO) or detrusor sphincter dyssynergia (DSD). There are two commonly used preparations of BoNTA: Botox (onabotulinumtoxinA) and Dysport (abobotulinumtoxinA). OBJECTIVE To compare the reported outcomes of onabotulinumtoxinA and abobotulinumtoxinA in the treatment of NDO, IDO, PBS, DSD, and BOO for adults and children. EVIDENCE ACQUISITION We performed a systematic review of the published literature on PubMed, Scopus, and Embase in the English language reporting on outcomes of both BoNTA preparations. Review articles and series with <10 cases were excluded. The articles were graded for level of evidence and conclusions drawn separately for data with higher-level evidence. EVIDENCE SYNTHESIS There is high-level evidence for the use of onabotulinumtoxinA and abobotulinumtoxinA in adults with NDO but only for abobotulinumtoxinA in children with NDO. Only onabotulinumtoxinA has level 1 evidence supporting its use in IDO, BOO, DSD, and PBS/interstitial cystitis. CONCLUSIONS We identified good-quality studies that evaluated onabotulinumtoxinA for all the indications described above in adults; such was not the case with abobotulinumtoxinA. Although this does not imply that onabotulinumtoxinA is more effective than abobotulinumtoxinA, it should be a consideration when counselling patients on the use of botulinum toxin in urologic applications. The two preparations should not be used interchangeably, either in terms of predicting outcome or in determining doses to be used.

Botulinum injections for the treatment of bladder symptoms of multiple sclerosis

Our objective was to demonstrate the efficacy and impact on quality of life of detrusor injections of botulinum neurotoxin type A in the treatment of bladder dysfunction in patients with multiple sclerosis.

An Updated Systematic Review and Statistical Comparison of Standardised Mean Outcomes for the Use of Botulinum Toxin in the Management of Lower Urinary Tract Disorders

CONTEXT Botulinum toxin A (BoNTA) has received regulatory approval for use in neurogenic detrusor overactivity (NDO) and overactive bladder (OAB), but it remains unlicensed in other lower urinary tract symptoms (LUTS) indications such as nonneurogenic LUTS in men with benign prostatic enlargement (LUTS/BPE), bladder pain syndrome (BPS), and detrusor sphincter dyssynergia (DSD). OBJECTIVE To compare statistically the outcomes of high level of evidence (LE) studies with placebo using BoNTA for LUTS indications; NDO, OAB, LUTS/BPE, BPS and DSD. EVIDENCE ACQUISITION We conducted a systematic review of the published literature on PubMed, Scopus, and Embase reporting on BoNTA use in LUTS dysfunction. Statistical comparison was made between high LE studies with placebo and low LE studies. EVIDENCE SYNTHESIS In adult NDO, there are significantly greater improvements with BoNTA in daily incontinence and catheterisation episodes (-63% and -18%, respectively; p<0.01), and the urodynamic parameters of maximum cystometric capacity (MCC), reflex volume, and maximum detrusor pressure (MDP) (68%, 61%, and -42%, respectively; all p<0.01). In OAB, BoNTA leads to significant improvements in bladder diary parameters such as daily frequency (-29%), daily urgency (-38%), and daily incontinence (-59%) (all p<0.02). The urodynamic parameters of MCC and MDP improved by 58% (p=0.04) and -29% (p=0.002), respectively. The risk of urinary tract infection was significantly increased from placebo at 21% versus 7% (p<0.001), respectively; the risk of intermittent self-catherisation increased from 0% to 12% (p<0.001). Men with LUTS/BPE showed no significant improvements in International Prostate Symptom Score, maximum flow rate, or prostate volume. There were insufficient data for statistical analysis in DSD, BPS, and paediatric studies. Low LE studies were found to overestimate the effects of BoNTA in all indications, but differences from high LE studies were significant in only a few parameters. CONCLUSIONS BoNTA significantly improves all symptoms and urodynamic parameters in NDO and OAB. The effect of BoNTA in treating LUTS dysfunction appears to be overestimated in lower as opposed to higher LE studies.

Histological changes in the urothelium and suburothelium of human overactive bladder following intradetrusor injections of botulinum neurotoxin type A for the treatment of neurogenic or idiopathic detrusor overactivity.

BACKGROUND We examined, for the first time in a prospective study, the histological changes in the urothelium and suburothelium of patients with neurogenic (NDO) or idiopathic detrusor overactivity (IDO) after one or repeat treatments with intradetrusor BoNTA. METHODS Flexible cystoscopic bladder biopsies were obtained from patients with urodynamically proven intractable spinal NDO or IDO before and 4 and 16 wk after one or repeat treatments with intradetrusor injections of BOTOX1 (NDO 300 U, IDO 200 U). Specimens were stained for haematoxylin-eosin and analysed blindly for inflammatory changes, fibrosis, hyperplasia, and dysplasia in the urothelium and suburothelium. Statistical comparisons were significant at p values less than 0.05. RESULTS Signs of chronic inflammation were found in 59.1% of baseline biopsies (65.6% of NDO vs. 50% of IDO, p=0.049), 67.6% of post-first biopsies and 86.4% after repeat injections. The two groups were comparable for degree of baseline inflammation, which did not change significantly after first injection and up to 16 wk after a third injection. Mild fibrosis was found in 2.2% of biopsies examined, equally before and after treatment, but not after repeat injections. No dysplasia or hyperplasia was identified. Eosinophils were identified more frequently in biopsies taken after repeat injections compared with the post-first injection and baseline biopsies (chi2=8.23, p=0.018). No difference existed between NDO and IDO bladders. CONCLUSIONS BoNTA injections do not appear to be producing significant inflammatory changes, fibrosis, or dysplastic changes in human bladder urothelium/suburothelium after a single injection and in a limited number of repeat treatment biopsies. The presence of eosinophils might be treatment-related, because they were mostly found in post-treatment biopsies.

Drug Insight: biological effects of botulinum toxin A in the lower urinary tract

Botulinum toxins can effectively and selectively disrupt and modulate neurotransmission in striated muscle. Recently, urologists have become interested in the use of these toxins in patients with detrusor overactivity and other urological disorders. In both striated and smooth muscle, botulinum toxin A (BTX-A) is internalized by presynaptic neurons after binding to an extracellular receptor (ganglioside and presumably synaptic vesicle protein 2C). In the neuronal cytosol, BTX-A disrupts fusion of the acetylcholine-containing vesicle with the neuronal wall by cleaving the SNAP-25 protein in the synaptic fusion complex. The net effect is selective paralysis of the low-grade contractions of the unstable detrusor, while still allowing high-grade contraction that initiates micturition. Additionally, BTX-A seems to have effects on afferent nerve activity by modulating the release of ATP in the urothelium, blocking the release of substance P, calcitonin gene-related peptide and glutamate from afferent nerves, and reducing levels of nerve growth factor. These effects on sensory feedback loops might not only help to explain the mechanism of BTX-A in relieving symptoms of overactive bladder, but also suggest a potential role for BTX-A in the relief of hyperalgesia associated with lower urinary tract disorders.

Suburothelial Myofibroblasts in the Human Overactive Bladder and the Effect of Botulinum Neurotoxin Type A Treatment

BACKGROUND An increasing body of evidence suggests a possible role of suburothelial myofibroblasts (MFs) in bladder mechanosensation and in the pathophysiology of detrusor overactivity (DO). OBJECTIVE To determine whether markers of MFs, including gap junction protein connexin43 (Cx43) and c-kit have altered immunohistochemical expression in the suburothelium of patients with neurogenic DO (NDO) or idiopathic DO (IDO) and whether this is affected by successful treatment of DO with botulinum neurotoxin type A (BoNTA). DESIGN, SETTING, AND PARTICIPANTS Patients with NDO (n=10) or IDO (n=11) were treated in a single-centre, open-label study of intradetrusor BoNTA injections. Control tissue was obtained from 10 patients undergoing pelvic-floor repair procedures who had no overactive bladder (OAB) symptoms. This study is registered with ClinicalTrials.gov, number NCT00662064. INTERVENTIONS Bladder biopsies performed with flexible cystoscopes were obtained from control subjects and from NDO and IDO patients before BoNTA treatment and at 4 wk and 16 wk after treatment. They were studied with quantitative immunofluorescence using antibodies to connexin 43 (Cx43), vimentin, and c-kit. MEASUREMENTS Differences in Cx43, vimentin, and c-kit immunoreactivity between control subjects and NDO or IDO patients (primary outcomes). Changes in NDO or IDO, Cx43 immunoreactivity, and c-kit immunoreactivity after BoNTA treatment (secondary outcomes). RESULTS AND LIMITATIONS Cx43 immunoreactivity was increased in both IDO and NDO patients compared to controls, but remained unchanged after BoNTA treatment. C-kit immunoreactivity was similar in NDO/IDO patients and controls and remained unchanged after BoNTA treatment. CONCLUSIONS Increased gap junction formation in the suburothelium has been demonstrated in biopsies from humans with DO. It is hypothesised that this change could have a significant role in the pathogenesis of the detrusor abnormality. Successful treatment of NDO or IDO does not appear to be associated with changes in the expression of Cx43 or c-kit on suburothelial MFs.

SILDENAFIL VERSUS INTRACAVERNOUS INJECTION THERAPY: EFFICACY AND PREFERENCE IN PATIENTS ON INTRACAVERNOUS INJECTION FOR MORE THAN 1 YEAR

PURPOSE To our knowledge comparative data on the effectiveness of and patient preference for intracavernous injection therapy and sildenafil are still not available. We evaluated the efficacy of sildenafil as well as patient preference in a group of impotent men on intracavernous injection for more than a year. MATERIALS AND METHODS Patients on intracavernous injection therapy for more than a year without neurological disease and/or a contraindication to sildenafil treatment were recruited for study. In phase 1 we determined the efficacy of 50 and 100 mg. sildenafil citrate at home. In phase 2 responders to sildenafil were asked to use the preferred dose orally for a month and choose intracavernous injection or sildenafil. In phase 3 patients were asked to continue either treatment for 3 more months. Patient preferences were reported at the end of phases 2 and 3. RESULTS Of the 180 men recruited 155 with a mean age of 56.4 +/- 12.6 years on intracavernous injection for a mean of 26 +/- 9 months accepted and were included in our series. Overall 116 men (74.8%) responded to sildenafil during study phase 1. After 1 month of treatment 71 responders (61.2%) preferred to continue with the oral drug, 31 (26.7%) returned to intracavernous injection and 14 (12.1%) used each drug alternately. Three months later 74 of the 116 responders (63.8%) preferred oral treatment and 38 (32.8%) chose intracavernous injection, while 4 (3. 4%) continued to use each treatment alternately. CONCLUSIONS Sildenafil is highly effective in intracavernous injection responders, although a certain group prefer to continue intracavernous injection. While sildenafil should be considered first line treatment, men with erectile dysfunction should be aware of all treatment options available because nonresponders to sildenafil may respond to intracavernous injection.

Diagnostic Steps In The Evaluation Of Patients With Erectile Dysfunction

PURPOSE The necessity for a thorough diagnostic evaluation for erectile dysfunction has been questioned after the availability of effective oral therapies. We determined the impact of the different diagnostic steps on the management strategy for erectile dysfunction. MATERIALS AND METHODS The study included all patients who presented at an andrology outpatient clinic during a 4-year period. Baseline evaluation included medical and sexual history, blood tests, physical examination and intracavernous injection test. Patients with normal initial screening were evaluated with specific diagnostic procedures. The results were analyzed to identify the diagnostic potential of each screening step separately. RESULTS Overall 1,644 patients presented at the clinic during the study period, of whom 368 (22.4%) were excluded from study due to severe psychiatric (5.2%) or cardiovascular (2.7%) disease, or to a history of erectile dysfunction less than 3 months in duration (14.5%). In the remaining 1,276 patients with a mean age plus or minus standard deviation of 56 +/- 14 years, and a mean duration of erectile dysfunction of 4.9 +/- 3.4 years medical history revealed erectile dysfunction associated medical conditions in 57%, blood tests identified previously undiagnosed medical conditions in 6.2%, and physical examination and the intracavernous injection test were diagnostic in 13.9% and 2.6%, respectively. Initial screening was negative in 259 cases (20.3%), in which specific diagnostic procedures identified an underlying vascular pathology in 165 (12.9%) and unfavorable penile geometry in 16 (1.3%). The remaining 78 men (6.1%) had no evidence of organic disease. CONCLUSIONS Baseline diagnostic evaluation for erectile dysfunction can identify the underlying pathological condition or erectile dysfunction associated risk factors in 80% of patients. Such screening may diagnose reversible causes of erectile dysfunction and also unmask medical conditions that manifest with erectile dysfunction as the first symptom. Specific diagnostic procedures may be limited in patients with primary erectile dysfunction or those without risk factors. Such clinical data support previously published guidelines for erectile dysfunction management.