Daniel Max Schmid

In this review we summarize the recent innovation of botulinum‐A neurotoxin (BoNT‐A) injections in the bladder as a potential new treatment option for idiopathic detrusor overactivity, refractory to conventional anticholinergic medication. BoNT‐A is produced by Clostridium botulinum and consists of a 150‐kDa neurotoxic protein that has the ability to cleave proteins within the nerve terminal. BoNT‐A is thereby able to prevent acetylcholine release at the presynaptic membrane, resulting in a chemodenervation of the detrusor muscle after intravesical injection; this can reduce symptoms in patients with refractory idiopathic detrusor overactivity. BoNT‐A intradetrusor injections might be an alternative to invasive surgery for patients in whom conservative measures and anticholinergic treatment have failed. Clinical studies with different dosages and injection protocols show success rates of 60–96% for neurogenic and non‐neurogenic detrusor overactivity, with wide variations in the duration of response. The drug is still under development for the indication of idiopathic detrusor overactivity, and is under ongoing investigation for long‐term efficacy and safety.

In this prospective, nonrandomized, ongoing study we evaluated the efficacy and safety of botulinum-A toxin injections in the detrusor muscle to treat patients with idiopathic overactive bladder resistant to conventional treatment, such as anticholinergic drugs. A total of 23 men and 77 women with a mean age of 63 years (range 24 to 89) with nonneurogenic overactive bladder, including urgency-frequency syndrome, and incontinence despite the administration of maximal doses of anticholinergics were consecutively treated with injections of 100 U botulinum-A toxin in the detrusor muscle at 30 sites under cystoscopic guidance. Micturition diary, full urodynamics, neurological status and urine probes were performed in all participants before treatment. Bladder biopsies were done only in cases of suspected bladder fibrosis or unclear findings. Special attention was given to reflex volume, maximal bladder capacity, detrusor compliance, post-void residual urine, urgency and frequency/nocturia. Clinical, urodynamic and quality of life assessments were performed at baseline, and 4, 12 and 36 weeks after botulinum-A toxin treatment. Overall after 4 and 12 weeks 88% of our patients showed significant improvement in bladder function in regard to subjective symptoms, quality of life and urodynamic parameters (p <0.001). Urgency disappeared in 82% of the patients and incontinence resolved in 86% within 1 to 2 weeks after botulinum-A toxin injections. Mean frequency decreased from 14 to 7 micturitions daily (-50%) and nocturia decreased from 4 to 1.5 micturitions. Mean maximal bladder capacity increased 56% from 246 to 381 ml, mean detrusor compliance increased from 24 to 41 ml/cm H(2)O and pretreatment detrusor instability (mean reflex volume 169 ml) resolved in 74% of patients. Mean volume at first desire to void increased from 126 to 212 ml and mean urge volume increased from 214 to 309 ml. There were no severe side effects except temporary urine retention in 4 cases. Only in 8 patients was the clinical benefit poor and analysis revealed preoperative low detrusor compliance. Mean efficacy duration +/- SD was at least approximately 6 +/- 2 months and then symptoms began to increase. Our results show that intradetrusor botulinum-A toxin injections may be an efficient and safe treatment option in patients with severe overactive bladder resistant to all conventional treatments.

Aims: The aim of this study is to assess neurogenic lesions of the somatomotor efferent nervous pathway to the urethral compressive musculature (UCM) by means of motor evoked potentials (MEP) and simultaneously recorded evoked pressure curves (EPC).Methods: Nine healthy subjects and 33 patients (15 spinal cord injury, 14 cauda equina lesion, and 4 multiple sclerosis (MS)) with neurogenic urinary incontinence were prospectively examined by means of urodynamics and electrophysiology. MEP responses from the UCM were evoked after transcranial (tc) and lumbosacral (ls) single pulse magnetic stimulation. A ratio out of tc/ls latencies was calculated to distinguish between central (i.e., spinal) and peripheral lesions. The mechanical UCM pressure responses ( = EPC) were recorded simultaneously with electromyographic (EMG) recordings using a microtip pressure transducer catheter with integrated bipolar surface electrodes.Results: In nine healthy subjects the central latency was 19.0 msec, the peripheral latency was 4.25 msec, and the ratio was 4.4. In patients with incomplete spinal cord lesion the central latency was significantly delayed (22.7 msec), whereas the peripheral latency was normal. The ratio (5.5) was increased. Thirteen of these 15 patients suffered from neurogenic incontinence. Patients with a complete spinal lesion showed no UCM reaction after tc stimulation, whereas peripheral responses were normal. Patients with MS showed significantly prolonged central latencies (25.5 msec). The increased ratio of 6.0 indicated a spinal lesion. Ten patients with incomplete cauda equina lesions and urinary incontinence had normal central latencies but prolonged peripheral latencies of 6.7 msec. The ratio of 3.4 indicated a lesion of the sacral caudal roots. In patients with complete cauda injury neither central nor peripheral responses could be evoked. Tc evoked mechanical pressure responses (i.e., contractions) from the UCM could only be recorded in intact or incompletely injured spinal and peripheral motor nervous pathways, whereas they could be evoked after ls stimulation only in cases with partially preserved sacral caudal roots independent of a spinal lesion.Conclusions: MEP and EPC from the UCM proved to be a well tolerated diagnostic tool in patients with neurogenic incontinence that distinguished central and peripheral lesions of the motor efferent pathways to the UCM.

In most spinal cord injured (SCI) patients the objective assessment of afferent neuronal pathways from the lower urinary tract and the recording of a disturbed urethral sensation and/or desire to void are still difficult. Viscerosensory evoked potentials (VSEPs) might be helpful, but they remain technically difficult to obtain and interpretation is delicate. As a new approach, sympathetic skin response (SSR) of the hand and foot were recorded after electrical stimulation of the posterior urethral mucosa. This technique should allow assessment of the integrity or deterioration of the autonomic afferent pathway. A total of 20 males and 8 females with SCI somatosensory incomplete 15, somatosensory complete 13 and 6 healthy male volunteers were prospectively examined. During urodynamic examination electrical stimulation (single square pulses of 0.2 ms, 2 to 3-fold sensory threshold, 60 mA in complete SCI patients) of the posterior urethra/bladder neck was performed using a bipolar electrode inserted into a microtip pressure catheter. SSR recordings of the right palm and sole were simultaneously taken using surface electrodes and were analyzed by an electromyography unit. Patient reports on evoked urethral sensations at individual sensory thresholds were simultaneously noted. Additionally, well-known electrophysiological measurements such as pudendal sensory evoked potential and urethral VSEP were recorded to check clinical assessed somatosensory and viscerosensory status, and to compare SSR results with these conventional methods. Electrical stimulation of the posterior urethra evoked clear urethral sensation and SSRs in normal subjects. In 14 of 15 sensory incomplete SCI patients with disturbed urethral sensation SSRs could be recorded as well. Electrically evoked urethral sensations resembled the subjective desire to void at full bladder reported by controls and patients. In 13 sensory complete SCI patients with loss of any urethral sensation SSRs could not be recorded even at maximal electrical stimulation strength. All subjects with electrically induced urethral sensation had positive evoked (supralesional) SSRs of the hand. However, none of the patients with absent urethral sensation presented SSRs. Simultaneously recorded VSEPs could not be recorded clearly in 5 patients and 2 control subjects, whereas SSRs delivered clear results in all controls and patients, matching their reports. SSR recordings above a spinal lesion level after urethral electrostimulation might provide a useful and technically simple objective diagnostic tool to assess integrity of autonomic (visceral) afferent nerves from the lower urinary tract. Somatosensory deficits are not always paralleled by viscerosensory loss and vice versa. In this study SSRs were superior to VSEPs, the latter being more difficult to record. The subjective sensations reported by subjects during stimulation could be confirmed in an objective way in 100% of cases by positive/negative SSR findings.