**3. Neuromodulation applications for urological conditions**

### **3.1 Overactive bladder, urgency urinary incontinence and urgency-frequency syndromes**

Bladder overactivity manifests in a number of urinary conditions, depending on the pathophysiology and associated conditions and symptoms. Overactive bladder (OAB), defined by a compelling frequent urge to void, is not a precession of urgency urinary incontinence (UUI), nor is it a more defined form urgency-frequency syndromes: these are all an overlapping number of conditions where evidence of overactivity of the detrusor muscle may or may not be demonstrable, but is subjectively reported by patients and often objectively measurable.

The treatment for these conditions is mainly conservative and medical, be it targeting the bladder muscle or the other offending factors that lead to the overactivity, followed by intradetrusor botulinum injections, which has attained a more defined role in the OAB treatment scheme. SNM is an established mode of treatment for cases of OAB, UUI and urgency-frequency syndromes that are refractory to medical treatment, and despite arguments and established results and testaments, is yet to be designated a more primary or first line place in the treatment of these conditions [95].

### *3.1.1 Mode of effect in OAB*

It has been shown that SNM has an established modulatory effect both on micturition reflexes and higher brain centers. The SNM electrical charging of sacral roots alters neural activity, stimulating somatic afferents that signal to higher brain centers and in part restore normal control over the bladder while also inhibiting certain sensory pathways to suppress reflex bladder hyperactivity. From animal models, evidence suggests this effect is achieved through SNM's inhibition of abnormal sensory input from the pudendal nerve and neuropathological C-fibers, affecting release of μ-opiods and glutamate and suppressing bladder reflexes [16].

### *3.1.2 SNM efficacy in OAB*

Efficacy of SNM is perhaps most studied and evidently reported in refractory OAB [96]. Analysis of five trials have analytically shown significantly higher success rates for SNM in treatment of OAB compared to standard medical treatment, and equally as efficacious as intradetrusor botulinum injections with less side effects

**229**

phases [9, 104].

*Neuromodulation in Urology: Current Trends and Future Applications*

associated with the latter including risk of post-injection urinary retention and

follow-up, 83% of implants were found to have sustained efficacy [68].

**3.2 Non-obstructive urinary retention and Fowler's syndrome**

urinary retention in a "neurologically-intact" patient is.

been shown to restore normal voiding activity [98].

**3.3 Neurogenic lower urinary tract dysfunction**

*3.2.1 Mode of effect*

effect of the micturition reflex [99].

In one prospectively conducted multicenter trial on OAB patients, the 5-year success rate of SNM was 67%, with the most common adverse event or reason for failure demonstrated to be an undesirable change in stimulation, followed by site pain and ineffectiveness of treatment [97]. The InSite trial reported on one of the longest prospective follow-ups for SNM implants for refractory OAB. At 36-months

Non-obstructive urinary retention (NOUR) is one of the main indications for SNM therapy. It denotes an unidentifiable mechanical cause that may obstruct urinary outflow from the urinary bladder, resulting in urinary retention. It may be the result of an established neurological disease, as is the case in the acute phase of spinal shock after spinal cord trauma, or in a minority of MS patients. Neither of these conditions are indicated for SNM treatment. However, chronic or recurrent

One form of NOUR is termed Fowler's syndrome after the neurophysiologist Professor Clare J. Fowler who first described it in 1985. It is a cluster of symptoms and findings identified in a typically young woman with unexplained urinary retention, increased electromyographic activity of the external urinary sphincter and its failure to relax, and some associations to other female syndromes have been described including polycystic ovaries. Application of SNM in these patients has

Researchers have used a number of animal models to establish the mode of effect SNM exerts in NOUR and Fowler's. Basic science evidence suggests that by blocking the inhibitory effect that abnormal afferent activity from the external urethral and anal sphincters has on micturition, restoration of the ability of the patient to void occurs. This stimulation is through blockade of the pudendal nerve's stimulatory

Lower urinary tract symptoms resulting from neurological disease are varied, and thus, determination of these symptoms and assessment is necessary before consideration for neuromodulation as not all symptoms would be ideally treated using this modality. Neurological diseases that have documented voiding dysfunction elements include SCI, MS, Parkinson's disease, cerebrovascular accidents, and diabetic neuropathy. Congenital neurologic disorders such myelomeningoceles are becoming apparent causes of voiding dysfunction in adults and SNM candidates, as management of these pediatric disorders improves, and these patients grow into the adult population [9]. Previously thought to lack efficacy in neurogenic LUTD because of lack of an intact nervous system, SNM is emerging as an efficacious therapeutic modality for this population of patients especially in reducing incontinence episodes [9, 100–104]. The concept of neural remodeling as a hypothesized effect of SNM has also been visited as a potential role in neurogenic LUTD, particularly in acute spinal shock

The ICS recommends SNM as an option for control of urinary symptoms in patients with stable neurological conditions who are at a low risk of developing

*DOI: http://dx.doi.org/10.5772/intechopen.92287*

urinary tract infections [41, 74].

### *Neuromodulation in Urology: Current Trends and Future Applications DOI: http://dx.doi.org/10.5772/intechopen.92287*

associated with the latter including risk of post-injection urinary retention and urinary tract infections [41, 74].

In one prospectively conducted multicenter trial on OAB patients, the 5-year success rate of SNM was 67%, with the most common adverse event or reason for failure demonstrated to be an undesirable change in stimulation, followed by site pain and ineffectiveness of treatment [97]. The InSite trial reported on one of the longest prospective follow-ups for SNM implants for refractory OAB. At 36-months follow-up, 83% of implants were found to have sustained efficacy [68].

### **3.2 Non-obstructive urinary retention and Fowler's syndrome**

Non-obstructive urinary retention (NOUR) is one of the main indications for SNM therapy. It denotes an unidentifiable mechanical cause that may obstruct urinary outflow from the urinary bladder, resulting in urinary retention. It may be the result of an established neurological disease, as is the case in the acute phase of spinal shock after spinal cord trauma, or in a minority of MS patients. Neither of these conditions are indicated for SNM treatment. However, chronic or recurrent urinary retention in a "neurologically-intact" patient is.

One form of NOUR is termed Fowler's syndrome after the neurophysiologist Professor Clare J. Fowler who first described it in 1985. It is a cluster of symptoms and findings identified in a typically young woman with unexplained urinary retention, increased electromyographic activity of the external urinary sphincter and its failure to relax, and some associations to other female syndromes have been described including polycystic ovaries. Application of SNM in these patients has been shown to restore normal voiding activity [98].

### *3.2.1 Mode of effect*

*Neurostimulation and Neuromodulation in Contemporary Therapeutic Practice*

As the name suggests, this modality is applied to areas in close proximity to target internal nerves. These include the pudendal nerve, be it through transcutaneous stimulation in the vagina in a female or in the perineal region in the male, or both the pudendal and sacral nerves when applied to the sacral skin. DGN is also a form of transcutaneous electrical nerve stimulation (TENS). It is advocated as a less invasive and low-cost neuromodulation system that can also be taught to patients

Multiple small-sized trials have demonstrated improvements in symptom scores and efficacy in patients with refractory OAB or MS with bladder hyperactivity. However, although it is safe, the durability of its effect has been called into

**3.1 Overactive bladder, urgency urinary incontinence and urgency-frequency** 

Bladder overactivity manifests in a number of urinary conditions, depending on the pathophysiology and associated conditions and symptoms. Overactive bladder (OAB), defined by a compelling frequent urge to void, is not a precession of urgency urinary incontinence (UUI), nor is it a more defined form urgency-frequency syndromes: these are all an overlapping number of conditions where evidence of overactivity of the detrusor muscle may or may not be demonstrable, but is subjectively

The treatment for these conditions is mainly conservative and medical, be it targeting the bladder muscle or the other offending factors that lead to the overactivity, followed by intradetrusor botulinum injections, which has attained a more defined role in the OAB treatment scheme. SNM is an established mode of treatment for cases of OAB, UUI and urgency-frequency syndromes that are refractory to medical treatment, and despite arguments and established results and testaments, is yet to be designated a more primary or first line place in the treatment of these

It has been shown that SNM has an established modulatory effect both on micturition reflexes and higher brain centers. The SNM electrical charging of sacral roots alters neural activity, stimulating somatic afferents that signal to higher brain centers and in part restore normal control over the bladder while also inhibiting certain sensory pathways to suppress reflex bladder hyperactivity. From animal models, evidence suggests this effect is achieved through SNM's inhibition of abnormal sensory input from the pudendal nerve and neuropathological C-fibers, affecting release of μ-opiods and glutamate and suppressing bladder reflexes [16].

Efficacy of SNM is perhaps most studied and evidently reported in refractory OAB [96]. Analysis of five trials have analytically shown significantly higher success rates for SNM in treatment of OAB compared to standard medical treatment, and equally as efficacious as intradetrusor botulinum injections with less side effects

**3. Neuromodulation applications for urological conditions**

reported by patients and often objectively measurable.

*2.4.3 Transcutaneous electrical nerve stimulation*

for self-application [5].

question [9, 94].

**syndromes**

conditions [95].

*3.1.1 Mode of effect in OAB*

*3.1.2 SNM efficacy in OAB*

**228**

Researchers have used a number of animal models to establish the mode of effect SNM exerts in NOUR and Fowler's. Basic science evidence suggests that by blocking the inhibitory effect that abnormal afferent activity from the external urethral and anal sphincters has on micturition, restoration of the ability of the patient to void occurs. This stimulation is through blockade of the pudendal nerve's stimulatory effect of the micturition reflex [99].

### **3.3 Neurogenic lower urinary tract dysfunction**

Lower urinary tract symptoms resulting from neurological disease are varied, and thus, determination of these symptoms and assessment is necessary before consideration for neuromodulation as not all symptoms would be ideally treated using this modality. Neurological diseases that have documented voiding dysfunction elements include SCI, MS, Parkinson's disease, cerebrovascular accidents, and diabetic neuropathy. Congenital neurologic disorders such myelomeningoceles are becoming apparent causes of voiding dysfunction in adults and SNM candidates, as management of these pediatric disorders improves, and these patients grow into the adult population [9].

Previously thought to lack efficacy in neurogenic LUTD because of lack of an intact nervous system, SNM is emerging as an efficacious therapeutic modality for this population of patients especially in reducing incontinence episodes [9, 100–104]. The concept of neural remodeling as a hypothesized effect of SNM has also been visited as a potential role in neurogenic LUTD, particularly in acute spinal shock phases [9, 104].

The ICS recommends SNM as an option for control of urinary symptoms in patients with stable neurological conditions who are at a low risk of developing upper tract deterioration from controlled voiding [4]. It is thus important to stress the need for proper assessment and continued evaluation of these patients as urinary retention, acute or chronic, could have consequences including urinary tract infection and renal failure [9].

### *3.3.1 Spinal cord injury*

SCI, especially complete transection, has long been accepted as a contraindication for sacral neuromodulation on the basis of a disturbed neural circuit. However, numerous reports have been reviewed that show promising results for SNM in the management of neurologically-stable SCI patients, even those with complete disruption [105]. In the acute phase of spinal shock where the bladder is atonic, SNM has been found to facilitate neurogenic remodeling as researchers theorize and demonstrate sustained SNM effects and remodeling in the brain [9, 104].

In a review of eight studies where SNM was employed in the management of lower urinary tract dysfunction in SCI patients, the success rate of the test phase was a shy 45%, but that later translated into a 75% success rate once the screened patients proceeded with IPG implantation. The treatment was well-tolerated and safe without any unexpected adverse events [106].

### *3.3.2 Multiple sclerosis*

MS is of special interest to neuro-urologists as the disease manifests with a spectrum of urinary symptoms and progresses with different patterns in this spectrum along the course of the disorder as well. Demyelination, the pathological hallmark of MS, eventually affects lower urinary tract nerves, resulting in dysfunction. Up to 80% of patients show neuro-urological symptoms within 10 years of diagnosis, most frequently bladder overactivity. As a matter of fact, voiding dysfunction is the first sign of the disease in up to 10% of patients [107].

Though not FDA approved, neuromodulation has been applied in MS patients for years, and its efficacy has been repeatedly demonstrated. SNM and PTNS have been shown in a number of series to decrease urinary symptoms and improve the quality of life of MS patients who demonstrate bladder overactivity; however, although SNM is approved for NOUR, it has not shown any benefit for MS patients demonstrating "hypoactive" urinary bladders with retention [107, 108].

What remains an important issue for MS patients being considered for SNM is appropriate patient counseling and communication with their treating physician or neurologist to assess the need for MRI examination in the future as well as stability of the disease, as disease progression and relapse would negatively affect the SNM outcomes [9, 105, 107].

### *3.3.3 Diabetic cystopathy*

Diabetic cystopathy is a condition that describes the neuromuscular effect long-standing diabetes has on the urinary bladder. Part of the condition stems from diabetic neuropathy, while another part may stem from vasculopathy affecting the detrusor muscle itself. In the application of neuromodulation to the control of overactivity symptoms resulting from diabetic cystopathy, promising results from series were overshadowed by a substantially higher than average rate of infections (17%) compared to the accepted average, as would be expected from any foreign body implantation in diabetic patients especially those with poor glycemic control [105].

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*Neuromodulation in Urology: Current Trends and Future Applications*

Chronic pelvic pain syndrome in males and its predominantly female counterpart interstitial cystitis/bladder pain syndrome are chronic conditions of pelvic pain and voiding dysfunction with a poorly understood etiology [109]. Off-label use of SNM in the treatment of these disorders is established with significant results, and similar to its unknown etiology, the way SNM provides subjective and objective improvements in bladder pain syndrome for example is yet to be clearly defined, with obvious differences in outcomes between IC/BPS and non-IC/BPS CPPS [110]. Many theories have been suggested for this mode of effect, from restoration of balance between excitatory and inhibitory signals in the pelvic plexus at different spinal levels as well as SNM's modulatory effect on bladder function and in turn pain. Another issue for consideration is the bilateral or multiple sacral root involvement in bladder and pelvic pain disorders, thus S3 stimulation may be insufficient to providing symptomatic relief, and some researchers have demonstrated efficacy

A multitude of studies and researchers are reporting on promising results for SNM in symptomatic management of CPP disorders, demonstrating improvements in pain indices and quality of life measures particularly relating to improvements in sleep, social life and sexual activity [110, 111]. With 10% of patients of IC/BPS reaching a severe stage refractory to conservative and other modes of management, SNM has found an emerging role in the therapeutic void for this condition. Success rates of SNM in IC/BPS have been reported to be high, north of 80% in some series, with apparent and significant objective improvements in pelvic pain and specific interstitial cystitis symptom scores as well as improvements in daytime frequency,

The ICS based on grade C evidence released a level III recommendation that designates SNM as an option for patients who are deemed non-responsive to conservative treatment measures of IC/BPS and non-IC CPPS [4]. However, large randomized controlled trials are lacking, perhaps in part due to the mixed spectrum of CPP disorders, both pathologically and symptomatically, heterogenous patient population, and unclear etiologies, and poorly understood differences in outcomes

The effects of neuromodulation, particularly SNM, on improving sexual function among female patients, and male patients to an extent, are becoming more evident in the literature [114]. Dysfunction of the pudendal nerve, an important nerve in sexual stimulation, has been demonstrated in both refractory OAB and

In a cohort of female patients who received SNM implants for OAB, urgencyfrequency syndrome or NOUR, improvements in both female sexual function index and quality of life indices were reported, though they were not correlated [116]. In another study on SCI female patients who had sexual dysfunction, there was a demonstratable improvement in the female sexual distress scale after neuromodula-

The argument is whether the improvements SNM provides with regards to urinary symptoms allows for a better sexual experience and confidence among patients or does SNM's effect on the pelvic floor musculature rejuvenise sexual function.

nocturia, urinary urgency, and average voided volume [112].

*DOI: http://dx.doi.org/10.5772/intechopen.92287*

**3.4 Special populations and effects**

*3.4.1 CPPS and IC/BPS*

of bilateral stimulation [14].

between the disorders [109, 110, 113].

*3.4.2 Sexual function*

NOUR [115].

tion therapy [117].
