Effects of intravesical onabotulinumtoxinA on bladder dysfunction and autonomic dysreflexia after spinal cord injury: role of nerve growth factor.

OBJECTIVE: To assess the significance of onabotulinumtoxinA (onabotA) intravesical administration in blocking autonomic dysreflexia (AD) response induced by cystometrogram (CMG) after T4 spinal cord transection (SCT). MATERIALS AND METHODS: Female rats were stratified into three groups: a sham group; a SCT-only group; and a SCT with onabotA treatment group. Each group was further subdivided into two subgroups: AD assessment, or nerve growth factor (NGF) assessment via enzyme-linked immunosorbent assay (ELISA). Three weeks after T4-SCT, all groups were assessed. Arterial pressure and heart rate were measured during and after CMG. NGF was also extracted from the bladder and the dorsal root ganglia (DRG) of the T4 root and quantified by ELISA. In the onabotA-treated group, 48 h before assessment, onabotA (1 mL, 20 U/mL in saline) was given using a urethral tube and was left indwelling for 30 min. Univariate anova was used to analyse the data and statistical significance was set at P < 0.05. RESULTS: The maximum voiding pressure and the number of uninhibited contractions were significantly lower in the group treated with intravesical onabotA than in the SCT-only group. Intravesical onabotA significantly blocked the dysreflexia response (high arterial pressure with bradycardia) induced by CMG after SCT. Intravesical onabotA also significantly lowered NGF concentrations in the bladder and the T4 DRG segment. CONCLUSIONS: The results of the present study showed that intravesical onabotA controls neurogenic detrusor overactivity and AD after SCT. The findings shed light on the potential benefits of intravesical onabotA treatment in patients with spinal cord injury, and also provide a novel mechanism for the control of AD via a minimally invasive treatment modality.

Mammalian target of rapamycin (mTOR) induces proliferation and de-differentiation responses to three coordinate pathophysiologic stimuli (mechanical strain, hypoxia, and extracellular matrix remodeling) in rat bladder smooth muscle.

Maladaptive bladder muscle overgrowth and de-differentiation in human bladder obstructive conditions is instigated by coordinate responses to three stimuli: mechanical strain, tissue hypoxia, and extracellular matrix remodeling.( 1,2) Pathway analysis of genes induced by obstructive models of injury in bladder smooth muscle cells (BSMCs) identified a mammalian target of rapamycin (mTOR)-specific inhibitor as a potential pharmacological inhibitor. Strain-induced mTOR-specific S6K activation segregated differently from ERK1/2 activation in intact bladder ex vivo. Though rapamycin's antiproliferative effects in vascular smooth muscle cells are well known, its effects on BSMCs were previously unknown. Rapamycin significantly inhibited proliferation of BSMCs in response to mechanical strain, hypoxia, and denatured collagen. Rapamycin inhibited S6K at mTOR-sensitive phosphorylation sites in response to strain and hypoxia. Rapamycin also supported smooth muscle actin expression in response to strain or hypoxia-induced de-differentiation. Importantly, strain plus hypoxia synergistically augmented mTOR-dependent S6K activation, Mmp7 expression and proliferation. Forced expression of wild-type and constitutively active S6K resulted in loss of smooth muscle actin expression. Decreased smooth muscle actin, increased Mmp7 levels and mTOR pathway activation during in vivo partial bladder obstruction paralleled our in vitro studies. These results point to a coordinate role for mTOR in BSMCs responses to the three stimuli and a potential new therapeutic target for myopathic bladder disease.

Efficacy of sacral neuromodulation in treatment of bladder pain syndrome: long-term follow-up.

AIMS: This study was sought to evaluate the efficacy and durability of sacral neuromodulation in the treatment of bladder pain syndrome (BPS) patients. METHODS: A retrospective chart review was performed of patients who had unilateral sacral nerve stimulator (InterStim®) for refractory BPS between June 2002 and December 2004. Patients were qualified for permanent implantation by showing ≥ 50% improvement in their bladder pain and voiding symptoms 1-week post-percutaneous nerve evaluation (PNE). Voiding diary was completed at pre-implantation, 1 year, and on the last visit. Urinary distress inventory short form was completed pre-implantation and on the last visit. Bladder pain was evaluated by visual analogue scale. Primary outcome was improvement in bladder pain. Differences among groups were compared by one-way ANOVA and t-test. Statistical significance was set at P ≤ 0.05. RESULTS: Twenty-one female patients diagnosed with BPS had PNE; 11 patients (52%) showed ≥ 50% improvement in their bladder pain and voiding symptoms and they consider candidates for permanent implantation (Table I), while 10 patients (48%) failed to show 50% improvement in their voiding symptoms or bladder pain (Table II). In those 11 patients who underwent permanent implantation, the average patient's age was 44.3 ± 8.9 years; average time since diagnosis was 3 ± 0.8 years; the average follow- up was 71.5 ± 9.3 months (Table III). There was significant improvement in the bladder pain and voiding parameters at 1-year follow-up, which was maintained at 5-year follow-up. There was continuous improvement in urgency (1.2 ± 0.68) at 1-year follow-up, and (0.98 ± 0.72) at the last visit. Average voided volume was also continuously improved from 242 ± 62.7 ml at 1-year follow-up to 276 ± 64.7 ml on the last visit. CONCLUSION: Sacral neuromodulation as part of multimodal treatment provides an effective long-term treatment option for sub-group of refractory BPS.

Association between stimulation parameters and loss of efficacy of selective sacral nerve root stimulation.

OBJECTIVES: This study sought to determine the association between stimulation parameters at the time of implantation and loss of efficacy on long-term follow-up. MATERIAL AND METHODS: Between 2002 and 2007, 143 patients underwent selective sacral nerve root stimulation at our center as a treatment for voiding dysfunction. Nine patients were explanted because of loss of efficacy. The patients' charts were retrospectively reviewed and compared with those of a well-matched group of 12 positive responders. A t-test was used to determine the differences in voiding parameters and stimulation parameters between both groups (at p < 0.05). RESULTS: The baseline amplitude levels in the loss of efficacy group were significantly higher than those of the control group (2.08 ± 0.35 V vs. 1.27 ± 0.25 V) (p= 0.008). The impedance levels were significantly higher in the loss of efficacy group than the control (1032.4 ± 181 Ω vs. 590 ± 44.6 Ω) (p= 0.025). CONCLUSION: High stimulation parameters at the time of implantation were associated with loss of efficacy at the long-term follow-up.

Mechanisms of action of sacral neuromodulation.

The lower urinary tract dysfunction encompasses voiding, postvoiding, and storage symptoms. Conventional treatment modalities include pharmacotherapy and behavioural therapy. Sacral neuromodulation (SNM) is a safe and minimally invasive treatment modality that has recently gained wide acceptance in the management of urinary urge incontinence, urge frequency, and nonobstructive urinary retention, in particular, among those patients with conditions refractory to conventional methods. We searched multiple electronic databases through June 30, 2009 for eligible studies. We examined published clinical and experimental studies concerning the mechanisms of action of SNM. In the first part of the manuscript, we describe the anatomy and functions of the lower urinary tract including the reflexes involved in its functions and then review the pathophysiology of major types of the lower urinary tract dysfunction. In the second part, we discuss different ways for SNM to control various types of voiding dysfunction. The lower urinary tract dysfunctions affect millions of people worldwide and have a severe impact on their quality of life. SNM offers a safe and minimally invasive modality in the treatment of voiding dysfunctions, especially in patients with conditions refractory to conventional therapies.

Effects of doxycycline on voiding behaviour of rats with bladder outlet obstruction.

OBJECTIVE: To examine the voiding behaviour changes in rats with bladder outlet obstruction (BOO) while inhibiting matrix metalloproteinase (MMP) activity with doxycycline, as increased MMP activity may be involved in obstruction-induced bladder hypertrophy. MATERIALS AND METHODS: Female Sprague-Dawley were divided into eight groups (three rats in each group): normal control (NC) +/- doxycycline, 3 weeks partial BOO (3WPBOO) +/- doxycycline, 6 weeks PBOO +/- doxycycline, and 3 weeks PBOO followed by 3 weeks de-obstruction (3WOD) +/- doxycycline. All rats received the same food and water and were on the same 12 h dark/light cycle housed in metabolic cages. Treatment groups were given doxycycline 15 mg/kg/day subcutaneously twice daily. The voiding variables measured were average voided volume (AV V) and voiding frequency (VF) in 24 h. After completion of the voiding behaviour studies, the rats were killed and their bladders were excised and weighed. RESULTS: The AV Vs were significantly increased (P < 0.05) in all study groups compared with the NC group except for the 3WPBOO-doxycycline and 3WOD-doxycycline groups. The VF was significantly increased (P < 0.05) only in the 3WOD-doxycycline group. The bladder weights were significantly increased after PBOO in all the study groups (P < 0.05), except for the 3WOD group. CONCLUSION: These data show that MMP inhibition may affect voiding behaviour during the response to BOO or its relief. This is the first clinical demonstration that interfering with a principal target of bladder muscle wall remodelling may have a direct effect on bladder function.

Canadian experience in sacral neuromodulation.

The application of sacral nerve modulation and stimulation has gained wide acceptance asa tool to enhance the control of voiding. The simplicity of the technique has made the therapy appealing for refractory cases of voiding dysfunction. The percutaneous screening test is mandatory for the success of the therapy. Long-term follow-ups have shown efficacy and safety inpatients with voiding dysfunction. Sacral nerve modulation is an effective modality in the treatment of various voiding and storage dysfunction. The tined lead offers a minimally invasive implant procedure. The simplicity of the procedure and the patient's sensory awareness help to ensure best lead placement. Furthermore, local anesthesia instead of general anesthesia allows faster patient recovery and reduces complications. Finally, sacral neuromodulation offers a modality in the management of patients with voiding dysfunction.

Mechanism of action of sacral nerve stimulation using a transdermal amplitude-modulated signal in a spinal cord injury rodent model.

INTRODUCTION: : Sacral neuromodulation (SNM) is an effective treatment modality for several urological problems, including neurogenic bladder. However, the invasiveness of this technique makes it unsuitable for many patients. We present a novel transdermal amplitude-modulated signal (TAMS) that may provide a non-invasive alternative to implantable SNM to treat neurogenic detrusor overactivity (NDO). METHODS: : In this study, we investigated the mechanism of action of non-invasive SNM using TAMS on our established spinal cord injury (SCI) animal model. We demonstrated that spinally transected rats develop urinary bladder hyper-reflexia after 3 weeks of SCI, indicated by the presence of uninhibited contractions, increased resting pressure, increased threshold pressure and increased maximum voiding pressure. RESULTS: : Short-term neurostimulation affected urodynamics parameters by significantly reducing the threshold pressure (p = 0.02). Spinal transection also increased calcitonin gene-related protein (CGRP) concentration in the L6 dorsal root ganglia; whereas, neurostimulation significantly reduced CGRP concentration in L6 (p = 0.03). CONCLUSION: : TAMS caused a reduction in NDO by inhibiting C-fibre activity.

Early versus late treatment of voiding dysfunction with pelvic neuromodulation.

INTRODUCTION: Pelvic neuromodulation is an established method of treating voiding dysfunction. Little is known about the pathophysiology associated with voiding dysfunction. Reports have suggested that a delay in treating patients with sacral neuromodulation therapy can impact the success rate of this type of treatment in voiding dysfunction. We examined patient response to pelvic neuromodulation when it was applied early versus late in the postdiagnosis of voiding dysfunction. METHODS: We conducted a retrospective study of 42 patients (38 women and 4 men) with voiding dysfunction who underwent surgery for implant with the Interstim (Medtronic, Minneapolis, Minn.). Prior to implantation, patients were required to pass a percutaneous nerve evaluation (PNE) over a 1-week period. Patients were observed for 20-48 months postimplantation. All patients recorded their voiding parameters at baseline, after screening and every 6 months thereafter. Twenty patients (in the early group) underwent implant surgery with the neurostimulator 2-4 weeks post-PNE, and 22 patients (the late group) had the device implanted 6-24 months post-PNE owing to local logistical circumstances. RESULTS: In the early group, 16 of 20 patients (80%) maintained a good response. In the late group, 13 of 22 (59%) patients showed a good response. Groups were well matched in terms of age, duration of voiding dysfunction and incidence of comorbidity. CONCLUSION: Patients who were delayed more than 6 months in receiving the neurostimulator implant showed a worse response than did patients who had the device implanted soon after PNE. This indicates the possibility of disease progression, which may limit the response to sacral neuromodulation.

Safety of MRI at 1.5Tesla in patients with implanted sacral nerve neurostimulator.

OBJECTIVES: Sacral neuromodulation has become an established method to treat voiding dysfunction. Currently the use of implanted sacral nerve stimulators is becoming more popular worldwide. Magnetic resonance imaging (MRI) is an important diagnostic tool for many medical and neurological disorders. Many radiology centers do not perform MRI examinations on patients with implanted sacral nerve stimulator. The basis for this policy is that potential hazards such as motion, dislocation or torquing of the implanted pulse generator (IPG), heating of the leads, and damage to the IPG may occur, resulting in painful stimulation. In contrast, many studies conducted on MRI at 1.5Tesla in patients with implantable devices have found the examination to be safe if the area to be imaged is out of the isocenter of the MRI scanner and other precautions are taken. METHODS: Eight MRI examinations at 1.5Tesla were conducted in areas outside the pelvis on six patients with implanted sacral nerve stimulator (InterStim neurostimulator; Medtronic, Inc, Minneapolis, MN, USA). Implanted pulse generators were examined before and after MRI procedures. All patients had their parameters recorded; then the IPGs were put to "nominal" status. Patients were monitored continuously during and after the procedure. After the MRI session, the site of the implanted device was examined and changes were reported. Devices were then re-programmed to their previous setup with the use of a programmer (model 7432; Medtronic, Inc). Voiding diaries were collected after MRI procedures and compared with previous records. RESULTS AND CONCLUSION: During the MRI session, no patient showed symptoms that required stopping the examination. There was no change in perception of the stimulation after re-programming of the implanted sacral nerve stimulator, according to patients' feedback. Devices were functioning properly, and no change in bladder functions was reported after MRI examinations. Finally, we hope that presenting these cases will encourage performance of more comprehensive studies on implanted sacral nerve stimulators on a larger patient population in the near future.

Impact of flow level on coronary flow velocity pattern. A doppler flow study in patients with first acute myocardial infarction.

Analysis of coronary flow velocity pattern has been used to assess microvascular function post acute myocardial infarction (AMI). This study sought to analyze whether the flow level has an impact on parameters of coronary flow velocity pattern. Parameters of coronary flow velocity pattern were determined at baseline and during increased flow due to maximal hyperemia induced by adenosine in 25 patients after PTCA for first AMI using Doppler flow wires. Patients were divided into those with depressed (global wall motion index (GWMI) > or = 1.5; n = 14) and those with preserved (GWMI < 1.5; n = 11) left ventricular (LV) function at 4 weeks. Coronary flow velocity pattern at rest was different between patients with depressed and patients with preserved LV function at follow-up. A difference in flow pattern between the groups remained at increased flow level. However, increase of flow altered parameters of flow pattern. Diastolic deceleration rate (DSR) increased for patients with preserved LV function (53.7+/-25.6 at baseline vs. 67.0+/-29.8 cm/s2 with adenosine) and depressed LV function (95.3+/-58.6 vs. 110.7+/-61.4 cm/s2, respectively, p = 0.0012). Induction of hyperemia resulted also in increased systolic and diastolic peak flow velocity and diastolic deceleration time (DDT). Higher flow had no impact on early systolic retrograde flow, systolic flow duration and diastolic-systolic velocity ratio (DSVR). The coronary flow velocity pattern allows prediction of LV function at 4 weeks after AMI. However, it should be considered that some parameters of the flow velocity pattern are affected by the coronary flow level.