b) Botulinum toxin
In a LOE1 study, the effects of botulinum toxin versus placebo was studied on DSD in 86 multiple sclerosis (MS) patients. The study employed a single transperineal injection of BoNT-A, 100 units in 4 cc normal saline, or placebo, into the striated sphincter with EMG guidance. The primary endpoint was post void residual volume at 30 days. The secondary endpoints included voiding and urodynamic variables. Results showed that a single injection of BTX did not decrease post-voiding residual volume in this group of MS patients. These findings differ from those in patients with spinal cord injury and may be due to lower detrusor pressures in MS patients.
In general, bethanechol chloride seems to be of limited benefit for detrusor areflexia and for elevated residual urine volume. Elevated residual volume is often due to sphincter dyssynergia. It would be inappropriate to potentially increase detrusor pressure when concurrent DSD exists.
• Bladder relaxant agents should be recommended for the treatment of reflex incontinence evoked by neurogenic detrusor overactivity in patients in whom IC alone is unable to control it ( A).
• Titration of the dosage of these drugs individually should be done to achieve maximum therapeutic effect and minimal side effect. If one drug is not tolerated, try another drug as it may have less side effects ( C/D).
• BoNT should be offered as a treatment option for neurogenic detrusor overactivity ( A).
• Vanilloid intravesical therapy still remains experimental and therefore is not recommended except within clinical trials (C/D)
• Further attempts for the treatment of NDO should be undertaken to develop the ideal drug in terms of good efficacy, tolerability and safety ( D).
• For decreasing outlet resistance in neurogenic bladder a-adrenergic antagonists may be used ( B/ C).
• BoNT may be considered for DSD in spinal cord injury patients ( B)
• For neurogenic sphincter deficiency no effective drugs are available up to now; further research is needed ( D).
• For detrusor areflexia no effective drugs are available up to now (IC remains the gold standard) ; further research is needed • Long-term a-adrenergic antagonists are
effective and well tolerated in patients with MS and suprasacral spinal cord lesion with neurogenic lower urinary tract dysfunction (LOE1)
• Data on the use of botulinum toxin (BonT) for DSD are conflicting. BoNT is probably safe and effective for the treatment of DSD in spinal cord injury patients (LOE2). However, on the basis of one LOE1 study, BonT does not provide significant benefit for the treatment of DSD in MS patients, • There is no adequately designed controlled
study of any drug for neurogenic sphincter deficiency.
• Bladder relaxant drugs, including oxybutynin, propiverine, trospium and tolterodine have a documented suppressive effect on incontinence by controlling overactive bladder, thereby improving storage function (LOE 1).
• However, all of these drugs presently available have considerably high incidence of side effects (dry mouth, constipation, urinary retention, etc.), which limits their usage. Tolterodine, propiverine, trospium and controlled-release oxybutynin have significantly less side effects compared to immediate-release oxybutynin (LOE 1). • High doses of OXY-XL seem safe and
effective in patients with neurogenic bladder (LOE 3)
• Although the oral application is the usual way, intravesical instillation or intrarectal (oxybutynin) may be an alternative (LOE 4). • Intravesical instillation of capsaicin/ resiniferatoxin has been reported to improve spinal reflex incontinence for several months after instillation (presumably blocking sensory input). Resiniferatoxin is preferable (LOE 3).
• Botulinum toxin injections into the detrusor muscle was reported to improve incon- tinence and increase functional bladder capacity in spinal cord injured patients with neurogenic DOA (LOE 1).
a) Electrical Neuromodulation
In the last decade sacral nerve neuromodulation has been confirmed as a valuable treatment option for patients with symptoms of overactive bladder. The success with sacral neuromodulation has increased the interest in other neuromodulation techniques. The current techniques of neuromodulation for treating overactive bladder – which includes detrusor overactivity of neurologic origin - are (a) anogenital electrical stimulation, (b) pudendal nerve stimulation, (c) sacral nerve neuromodulation, (d) percutaneous posterior tibial nerve stimulation (Stoller afferent nerve stimulation, SANS), (e) magnetic stimulation and f) deep brain stimulation
It is not really known how neuromodulation works, however, there is strong evidence that neuromo- dulation works at a spinal and at a supraspinal level .For more details about possible mechanism of actions see ICI report 2005
It has been shown that electrical stimulation of pudendal nerve afferents can inhibit bladder contractions in patients with SCI, and bladder capacity can be increased by continuous  as well as conditional stimulation  (LOE3). Implants such as the InterStim® system have made this treatment modality commercially available (see sacral nerve stimulation). Common to these implantable systems is that they use continuous stimulation. Detrusor inhibition is in principal only necessary during an involuntary contraction and, thus, stimulation could be turned off between contractions. Such a stimulation scheme could have a number of advantages. Power consumption may be decreased and, thus, extend battery lifetime. Furthermore, continuous stimulation of a reflex may lead to habituation, which would be minimized or prevented by conditional stimulation. Hansen et al. examined the effect of the automatic, event driven electrical stimulation of pudendal nerve afferents on bladder capacity in patients with SCI. The study included 2 women and 14 men older than 18 years with NDO, bladder capacity below 500 ml and complete or incomplete suprasacral spinal cord injury. Detrusor pressure (Pdet) was recorded during ordinary, natural bladder filling. In a similar subsequent recording Pdet was used to trigger electrical stimulation when pressure exceeded 10 cm H2O. Of the 16 patients enrolled in this study 13 had increased bladder capacity together with a storage pressure decrease as a result of automatic, event driven electrical stimulation. During stimulated filling Pdet never exceeded 55 cm H2O. Thus, storage pressure was sufficiently low to prevent kidney damage. An average bladder capacity increase of 53% was achieved (LOE 3)
3. CHRONIC PUDENDAL NERVE STIMULATION
Direct pudendal nerve stimulation has beneficial effects on numerous pelvic floor function impairments such as urinary and/or fecal incontinence, retention, and constipation. In preceding literature the implant technique required a fairly complex and invasive surgery, although recent advances with percutaneous placement of the lead through an introducer have made the procedure much less invasive. Spinelli et al. performed staged procedure similar to that of sacral neuromodulation (SNM) to place tined lead near the pudendal nerve, using neurophysiological guidance. They named this approach chronic pudendal nerve stimulation (CPNS).
Fifteen neurogenic patients (eight male, seven female) with symptoms of urge incontinence due to neurogenic overactive bladder underwent CPNS. All patients had complete neurophysiological and urodynamic evaluation at baseline and follow-up and were asked to complete voiding and bowel diary for 7 days. During screening, average number of incontinent episodes per day decreased from 7+/-3.3 to 2.6+/-3.3 (P<0.02, paired t-test). Eight patients became continent, two improved by more than 88% (from 9 to 1 daily incontinence episodes) and two patients reduced the number of incontinence episodes by 50%. The implantable pulse generator (IPG) was subsequently implanted in those 12 patients. Three patients without improvement did not continue to second stage. In implanted patients with 6 months follow-up, urodynamic evaluation showed an objective improvement in the maximum cystometric capacity which increased from 153.3+/ -49.9 to 331.4+/-110.7 ml (P<0.01, paired t-test). The maximum pressure decreased from 66+/-24.3 to 36.8+/-35.9 cmH2O (P=0.059, paired t-test). Eight patients reported significant improvement in bowel function (LOE3).
4. POSTEROR TIBILAL NERVE STIMULATION
Posterior tibial nerve stimulation was described 20 years ago as a minimally invasive treatment for urge incontinence due to neurogenic detrusor overactivity (NDO) in spinal cord injury (SCI) patients. Interestingly, the site involves the Sanyijioa (Sp6) point use in Chinese acupuncture for urinary incontinence problems.
Pudendal nerve afferent (S2 to S4) are well know to suppress NDO but it is not intuitively obvious that PTN afferents should have similar effect. However, the PTN is derived from L4 and L5 and S1 to S3 nerve roots and therefore shares common roots with those serving bladder functions. In few reports, SCI and Parkinson patients have been treated with PTN because of NDO and neurogenic incontinence. PTN seems to increase cystometric bladder capacity, enhance bladder volume at which hyperreflexic contraction and associated leakage occurs [70,71] (LOE3).
b) Repetitive transcranial magnetic stimulation Repetitive transcranial magnetic stimulation (rTMS) of the motor cortex induces a long-lasting modulation of spinal cord excitability . Thus, it represents a potentially useful tool for the treatment of neurogenic urinary disturbances. Centonze et al.  investigated the effects of high frequency (5 Hz) excitatory rTMS over the motor cortex on LUT dysfunction in a population of 10 MS patients complaining of urinary symptoms. All but one of the patients reported an improvement of voiding phase LUT symptoms and a significant reduction of post void residual volume. In patients with pure detrusor underactivity, this finding seems to be produced by a better contraction of the detrusor muscle, with consequent increase of Pdet@Qmax and Qmax.
Notably, a similar finding was reported in female Fowler’s syndrome patients after sacral neuro- modulation, a procedure that probably shares some central actions with rTMS. In patients with DSD, on the other hand, rTMS produced negligible effects, although the observation of a reduction of Pdet@Qmax seems to suggest a better relaxation of the urethral sphincter (LOE3).
c) Deep brain stimulation
1. SUBTHALAMIC NUCLEUS DEEP BRAIN STIMULATION
A large proportion of patients suffering from Parkinson’s disease presents with urinary dysfunction including urgency, increased frequency or incontinence as predominant symptoms . Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has been established as a surgical treatment of motor symptoms in Parkinson’s disease patients . However, data from experimental urodynamic measures in men  and animal models  have also demonstrated a significant influence of STN-DBS on urinary bladder function. In these studies, the main effect of STN- DBS appeared to be a normalization of urodynamic parameters in the storage phase with a delayed first desire to void and an increased bladder capacity. Herzog et al. aimed at investigating the effect of STN- DBS on the neural mechanisms underlying cerebral bladder control. Using PET to measure changes in regional cerebral blood flow (rCBF), 11 patients with bilateral STN-DBS were studied during urodynamic bladder filling in STN-DBS ON and OFF condition. A filled bladder led to a significant increase of rCBF in the anterior cingulate cortex, which was further enhanced during STN-DBS OFF.
A significant interaction between bladder state and STN-DBS was observed in lateral frontal cortex with increased rCBF when the bladder was filled during STN-DBS OFF [78,79] (LOE3).
2. THALAMIC DEEP BRAIN STIMULATION
The precise mechanisms underlying cerebral regulation of lower urinary tract function are still poorly understood. Essential tremor (ET) is not known to induce lower urinary tract symptoms (LUTS) or neuropathological changes in the thalamus. Consequently, DBS in patients with ET offers the unique opportunity to investigate the role of the VIM nucleus in lower urinary tract function. Kessler at al.  evaluated the effect of thalamic DBS on urodynamic parameters in patients with ET. Seven patients were examined (two females, five males) with ET 15–85 mo after implantation of DBS leads into the ventral intermediate nucleus of the thalamus. They compared urodynamic parameters during thalamic DBS (ON state) and 30 min after turning the stimulator off (OFF state). In the ON compared with the OFF state, there was a significant decrease in bladder volume at first desire to void (median, 218 ml vs. 365 ml, p = 0.031), at strong desire to void (median, 305 ml vs. 435 ml, p = 0.031), and at maximum cystometric capacity (median, 345 ml vs. 460 ml, p = 0.016). No significant differences between the ON and OFF state were detected for changes in detrusor pressure during filling cystometry, bladder compliance, maximum detrusor pressure, detrusor pressure at maximum flow rate, maximum flow rate, voided volume, and postvoid residual (LOE3).
• Electrical neuromodulation mostly is not the first line treatment for neurogenic detrusor overactivity. There are some limited reports showing that it may be beneficial (LOE 3).
• Automatic, event driven electrical stimulation in the treatment of NDO is feasible (LOE 3). • Chronic pudendal nerve stimulation is
feasible. Neurophysiological guidance seems to be mandatory to place the lead near the pudendal nerve either using perineal or posterior approach (LOE3).
• Enhancing corticospinal tract excitability by rTMS might be useful to ameliorate detrusor contraction and/or urethral sphincter relaxation in MS patients with bladder dysfunction (LOE3).
• Thalamic deep brain stimulation resulted in an earlier desire to void and decreased bladder capacity, suggesting a regulatory role of the thalamus in lower urinary tract function (LOE3).
• STN-DBS appeared to be a normalization of urodynamic parameters in the storage phase with a delayed first desire to void and an increased bladder capacity (LOE3).
d) Electrical stimulation of the pelvic floor musculature
1. BACKGROUND(See ICI 2002 page 740)
The aim of electrical stimulation in patients with neurogenic urinary stress incontinence is to improve the function, which are strength and/or timing of the pelvic floor muscle contraction.
Electrical stimulation is provided nowadays mostly by portable battery powered stimulation. It offers a seemingly infinite combination of wave forms, frequencies, intensities, electrode placements etc. In patients with incomplete denervation of the pelvic floor muscle and of the striated sphincter, electrical stimulation via anal or vaginal plugs performed over months, may improve pelvic floor function, and may thus improve incontinence. The incompleteness of the lesion should be as such that the patient is able to contract voluntary the pelvic floor, even if such contraction is weak.
RECOMMENDATION (Unchanged since ICI 2002)
e) Intravesical electrical stimulation (IVES)
BACKGROUND(read ICI 2002 page 741 and following)
The afferent stimuli induced by IVES travel along afferent pathways from the LUT to the corresponding cerebral structures. This “vegetative afferention” results in sensation of bladder filling/urge to void, with subsequent enhancement of active contractions, and possibly also in voluntary control over the detrusor. Feedback training is mediated by enabling the patient to observe the change of the detrusor pressure on a water manometer, which enables the patient to notice when a detrusor contraction takes place. This also facilitates voluntary control.
The technique involves a catheter with a stimulation electrode, introduced into the bladder and connected to the stimulator. Saline (0,9 %) is used as the current leading medium within the bladder. The neutral electrode is attached to the skin in an area with preserved sensation, usually in the lower upper abdomen.
Intravesical electrical stimulation of the bladder (IVES) is still a controversial therapy for patients with neurogenic detrusor dysfunction.
It is worthwhile to apply intravesical electrostimulation, bearing in mind inclusion and exclusion criteria, especially to verify functional afferent fibers within the bladder and the cortex. Intravesical electrotherapy is able to improve neurogenic bladder dysfunction, primarily by stimulating a-delta mechanoafferents inducing bladder sensation and the urge to void and consequently increasing the efferent output with improvement of micturition and conscious control. Therefore IVES is the only available option to induce/improve bladder sensation and to enhance the micturition reflex in incomplete central or peripheral nerve damage. However, proper indication is crucial and this type of therapy should only be applied in those with afferent fibers between the bladder and the cortex, proved by the evaluation of viscerosensory cortical evoked potentials. If these conditions are respected, IVES can be effective. In ICI 2002 30 studies about IVES have been reviewed. The conclusions for this consultation are not different from what was given in 2002.
Techniques of electrical stimulation involving surgery • In patients with incomplete denervation of
the pelvic floor muscle and the striated sphincter, electrical stimulation via anal or vaginal plugs performed over months, may be an option to improve pelvic floor function, thus improve incontinence. The incom- pleteness of the lesion should be as such that the patient is able to contract voluntary the pelvic floor even if this is weak ( C/D)
• Although from the theoretical point of view and based on limited personal clinical experiences electrical stimulation via anal or vaginal plugs could be able to improve the strength of pelvic floor musculature, including that of the striated sphincter muscle, there is no study published which deals with this matter (LOE 4)
• If pharmacotherapy fails to relax the hyperreflexic detrusor, electrical neuromo- dulation may be optional in patients with neurogenic detrusor ( C/D)
• Although the setup for automatic, event driven electrical stimulation is not suitable in a clinical setting, the treatment modality is promising and it warrants further investigation ( D).
• Further studies on chronic pudendal nerve stimulation must be carried out to identify the best stimulation parameters and to verify the long term results ( D)
• The thalamus may be a promising target for the development of new therapies for lower urinary tract dysfunction. Further investigation on this matter is critical before one speculates, that the thalamus will emerge as a target for treatment of lower urinary tract symptoms such as urinary urgency and bladder pain ( D).
• STN-DBS might ameliorate bladder dysfunction and that this modulation may result from facilitated processing of afferent bladder information (D).