8. Management of the Suprapontine Neurogenic Lower Urinary Tract Dysfunction
KeywordsPharmacotherapyAntimuscarinicsMirabegronBotulinum toxinCannabinoid agonistsPercutaneous tibial nerve stimulationTranscutaneous tibial nerve stimulationBladder catheterism
In the case of suprapontine lesions, the most common bladder dysfunction is neurogenic detrusor overactivity. Antimuscarinics can be considered the mainstay of treatment, while other therapies like cannabinoids look promising. Intravesical injection of botulinum toxin can be considered the main second-line treatment in case of failure of antimuscarinics. Conservative treatments should be associated with drugs. Cognitive effects of therapy shall be bared in mind for all the therapies with systemic absorption.
As specified in the chapter dedicated to the pathophysiology of LUTD in suprapontine lesions, the predominant clinical condition consists of UI due to detrusor overactivity (DO), associated to detrusor underactivity (DU) in a minority of patients. Sphincter incompetence is quite infrequent as well, and the clinical phenotype consists of urge incontinence too [1–5].
The pharmacotherapy of incontinence in suprapontine lesions consists of the typical spectrum of drugs commonly used in OAB; their integration with conservative treatment is often the key of successful treatment, as these patients can experience limitations in movements and/or cognitive impairment concurring to the occurrence and maintaining of incontinence .
Micturition in suprapontine lesions is usually coordinated, and then in this category of patients the symptom relief is the primary intent of treatment. In general, the evidence base for their use in the neurogenic bladder is limited, and data about the suprapontine disease are scarce and usually limited to Parkinson’s disease (PD) and cerebrovascular accidents (CVA) .
Special attention is needed in case of cognition impairment, as antimuscarinics can cause deterioration in memory or onset of confusion.
Oxybutynin hydrochloride has shown adequate efficacy and safety profile in Parkinson’s disease and multiple sclerosis, when used with titration criteria, until the dosage of the maximum therapeutic effect/tolerability balance is reached, even at a dosage of 30 mg per day .
When compared to oxybutynin, propiverine shows similar urodynamic and symptomatic improvement, but with a lower incidence of dry mouth .
Trospium chloride has shown urodynamic and clinical improvement in neurogenic detrusor overactivity (NDO) while not passing the blood-brain barrier (BBB). This is at least in theory an advantage for suprapontine lesions in case of cognitive impairment.
Solifenacin has been extensively studied in neurogenic DO, mostly in MS and spinal cord injuries, showing efficacy in urodynamic parameter improvements (first desire, volume at first involuntary contraction, maximum cystometric capacity), symptom relief and reduction of incontinence. A trial also exists, addressing the reduction of micturitions/24 h in PD pts. with OAB. In this study, the reduction in incontinence episodes is a secondary endpoint, while cognitive effects were not explored .
Very few data exist about darifenacin and fesoterodine in NDO.
Association of two different AM (usually a combination of oxybutynin, tolterodine and trospium) has shown to be effective and well tolerated, but data are limited to understand if the safety profile is increased .
Only one study has explored the eventuality of reducing the cognitive effects of AM by the use of central acetylcholinesterase inhibitors. The results of the Mini-Mental State Examination (MMSE) and ADAS-cog led the authors to conclude that this association could be an option in case of association of dementia and OAB .
Mirabegron is the only representative of a new family of drugs addressing OAB. Mirabegron is a β3 agonist with adequate selectivity (even if not exclusive) for bladder adrenoceptors.
Several reports exist about NDO in case of SI and MS, while data about suprapontine DO are more sparse. We could identify at least one study by Chen who showed symptom improvement in the absence of modifications of PVR and voided volumes, in 66 patients with CVA, PD, and dementia. Only two dropouts were registered due to the absence of therapeutic effects [13, 14].
Mirabegron should not produce cognitive impairment. β3 Receptors are present in the brain, but their function is still unclear.
8.4 Cannabinoid Agonists
Oral cannabinoid agents have shown a relaxing effect on bowel and bladder, tested in open-label as well as randomised clinical trials in SM patients. Specific data about suprapontine diseases are missing; experimental studies suggest that exocannabinoids and endocannabinoids could act at urothelial level, regulating afferent transmission [15–18].
8.5 Botulinum Toxin
Intravesical administration of onabotulinumtoxinA is a well-established second-line therapy when AM fails. In randomised multicentre trial complete continence was achieved in 36–38% of pts. with a 200UI toxin (40–41% with 300UI), while single-centre studies and one real-life study showed higher success rates. The therapy produces a significant quality-of-life improvement [19–21].
Focusing on suprapontine diseases, the most studied pathologies were Parkinson’s disease and cerebrovascular accident. In these patients BotoxA showed symptom and urodynamic efficacy. Data about long-term efficacy are rare: in extension study of registration trials, QoL was maintained at 3 years with repeat injections [24–27].
The treatment is overall safe, with urinary retention needing de novo CIC as the most concerning side effect (30–47%) [19, 21]. Haematuria and UTI are minor side effects, while the most serious event of generalised fatigue was observed in 0.005% only of cases, spontaneously resolving in 3–4 weeks [21–23].
8.6 Percutaneous and Transcutaneous Tibial Nerve Stimulation
Different pathologies of the central nervous system can cause neuro-urological symptoms. The neuro-urological symptoms depend on the location of the disease and the extent of the neurological lesion. Correctly, the suprapontine lesions are characterised by the interruption of inhibitory inputs to the CPM (pontine micturition centre); pathologies such as cerebrovascular lesions, Parkinson’s disease, tumours and traumatic brain injury and multiple sclerosis (depending on the location and severity of the lesion), determine an uncontrolled detrusor activity that results clinically in a neurogenic overactive bladder with symptoms such as voiding frequency, urgency, urge incontinence and nocturia. For example, in patients with Alzheimer’s disease, around 25% is reached, and up to 100% in patients who have advanced sclerosis. Neurogenic dysfunctions of the low urinary tract (NLUTD) substantially compromise the quality of life of the neuro-urological patient.
Percutaneous tibial nerve stimulation (PTNS) is a neuromodulation technique for treating symptoms of the lower urinary tract, obtained by electrical stimulation of the posterior tibial nerve. It is introduced as an alternative treatment for all those patients who are resistant to conservative therapies. The first to study its effects in 1983 was McGuire , who observed some improvement in symptoms in patients with lower urinary tract dysfunction (LUTS), stimulating the posterior tibial nerve and the common peroneal nerve, with adhesive electrodes. He demonstrated that transcutaneous electrical stimulation of the posterior tibial nerve could eliminate detrusor overactivity on a neurogenic basis. Subsequently, in the 1990s Stoller  and collaborators improved a treatment protocol and described a transdermal stimulation called Stoller afferent stimulation (SANS), a percutaneous stimulation of the posterior tibial nerve for the treatment of overactive bladder (OAB).
The mechanism of action is still unclear , but it is assumed that PTNS modulates the signals arriving and departing from the bladder (S2–S3) with afferent and efferent stimulation, through the sacral plexus; not only there are probably central-type paths for which stimulation is afferent retrograde, but there would also be a plastic reorganisation of the cortical network triggered by peripheral neuromodulation .
The posterior tibial nerve is in close association with the posterior tibial artery and is a mixed nerve containing motor and sensory fibres, which originates from the L4–S3 nerve roots; these same roots innervate the detrusor, the urinary sphincter and all the pelvic floor muscles.
The point where the needle is introduced was already known by traditional Chinese medicine , the SP6 point, as the point for bladder regulation and to relieve pelvic symptoms. A recent study by Yang et al.  however would have shown how the stimulation of the BL33 point (very close to S3) is equally effective in inhibiting the overactive bladder.
After positioning the needle, an electrode is placed on the ipsilateral heel bone. The needle and the electrode are both connected to a low-voltage stimulator of about 9 V. The generator that delivers the electrical impulse has fixed stimulation parameters: 200 μs pulse range, 20 Hz pulse frequency and variable stimulus intensity between 0.5 and 9 mA, respecting the patient’s tolerance threshold. To confirm the correct positioning of the needle, the power of the stimulus is slowly increased until the bending of the big toe and/or the waving of the other fingers is obtained. Furthermore, patients report a sensitive response to stimulation, such as tingling in the soles of the feet or fingers . The commonly used protocol involves a session per week lasting about 30 min for 10–12 weeks; in this regard, there are studies in the literature that show the same effectiveness, in less time, for more frequent applications [33, 34]. The results seem to depend on the number of stimulations performed but not on time elapsed since the start of the stimulation programme.
The more significant advantage of this technique is that it is minimally invasive; it is not a surgical technique and does not require a permanent stimulation implant as in sacral neuromodulation. The efficacy and safety of sacral neuromodulation techniques (SNM) and percutaneous tibial nerve stimulation (PTNS) were assessed in a recent review : the SNM proves more active, with an improvement rate of symptoms of LUTDs between 61% and 90% while the PTNS rate has a range of around 59–74%. SMN also shows long-term efficacy compared to PTNS, on which unfortunately there are no studies, in this review, on long-term follow-ups, although a 2018 study by Vecchioli-Scaldazza et al.  would show that the association of TPNS and solifenacin may have better and more long-term effects than with PTNS therapy alone. The substantial difference between the methods therefore lies in the safety parameters: in NMS there are no significant complications but the most common adverse event, estimated at 15% up to 42%, is pain in the implant; other complications related to surgery and implantation of the stimulator are related to the migration of the same (with consequent reoperation) or the rupture of the cables or a possible infection. Studies on TPNS instead do not report any adverse event and no complication; the only events reported in the studies report minor bleeding and a temporary feeling of pain in the needle application area. There are no surgical procedures required to solve these complications.
In recent years we have witnessed an evolution of the devices for sacral neuromodulation and an attempt has been made to solve the safety issue by implanting increasingly miniaturised electrodes, thus opting for a minimally invasive surgical treatment. The electrode, in this case, is connected to a wireless Bluetooth system , which allows it to be recharged and used by an external device. In 2018, AUA proposed a system to the ICS assembly that does not even foresee an external generator. MacDiarmid and collaborators  presented a preliminary report of a 12-week prospective, multicentre study on a new implantable system; the device is in titanium, is battery powered and of the size of a coin that can be programmed for home treatment of PTNS. Despite the research efforts, any implant, even the most miniaturised one, is not yet compatible with NMR. PTNS instead, not envisaging any permanent implant, is the only therapy, to date, that does not set these limits. The need to use an NMR-compatible technique is fundamental in the treatment of neurological patients with lower urinary tract dysfunctions on which urinary symptoms have a severe impact on the quality of life. In neurological patients it is the localisation and nature  of the neurological lesion that determine the level of dysfunction. The prevalence of neurogenic dysfunction of the lower urinary tract (NLUTD) depends on the neurological disorder; for example in patients with Alzheimer’s disease approximately 25% is reached and up to 100% in patients who have advanced multiple sclerosis. NLUTDs represent a significant impairment  in the daily life of the neuro-urological patient, substantially compromising the quality of life of the patient.
The use of electrical stimulation in NLUDT is based on a study by Sundin et al.  of 1974 in which it is shown that electrical stimulation of the pudendal nerve causes an inhibitory response on the bladder detrusor, in cats. This technique later evolved considerably and was improved and extended to different stimulation areas and is still used as transcutaneous electrical nerve stimulation for the treatment of various neuro-urological dysfunctions. A systematic review of the literature by Gross et al.  shows that electrical stimulation determines a positive and safe effect even in neurological patients with LUDT. Concerning PTNS, the number of reports is scarce, especially for patients with a neurological bladder. A trial by Amarenco and colleagues  shows an acute effect of PTNS on urodynamics in neuro-injured patients, all with symptoms of overactive bladder syndrome (multiple sclerosis, Parkinson’s disease and spinal cord injury); during electrical stimulation there is a significant increase in volume at the first involuntary detrusor contraction and an increase in cystometric capacity. As already pointed out previously, the urinary tract dysfunction is determined by the area and nature of the lesion: for example, the suprapontine lesions  will see a predominance of symptoms linked to bladder filling with detrusor overactivity. A publication by Phé et al.  on the treatment of PTNS on patients with multiple sclerosis illustrates the effectiveness of treatment in filling symptoms and urodynamic improvement. It reports data from a multicentre study on 70 patients with MS and overactive bladder symptoms. All patients received tibial nerve stimulation for 20 min a day for 3 months. Clinical improvement of symptoms was assessed based on criteria of improvement of frequency/urgency symptoms, patient-self-reported symptoms, bladder control and increased quality of life; in 2017 Canbaz Kabay et al.  went the extra mile in treating patients affected by multiple sclerosis with detrusor overactivity (DO) for up to 12 months. He shows that the results obtained with a 3-month treatment are preserved for up to 12 months in patients enrolled in his study. Patients are treated at intervals of 14 days for 3 months, then at an interval of 21 days for the following 3 months, and finally at an interval of 28 days. The protocol used by Kabay involves the introduction of a 26-gauge needle inserted about 5 cm cranially to the medial malleolus and an electrode on the ipsilateral heel bone. The stimulation is applied unilaterally using 200 μs pulse range, 20 Hz pulse frequency and variable stimulus intensity between 1 and 5 mA, observing the tolerance threshold of the patient and in any case capable of evoking foot bending or waving of the fingers. All parametric variables of daily micturition, frequency, urgency and nocturia and episodes of incontinence appear significantly improved compared to the baseline, as well as the perception of the quality of life.
Some symptoms of the lower urinary tract such as urgency, daytime frequency and nocturia are also very common in autonomic disorder in patients with Parkinson’s disease (PD). Urodynamic alterations and functional abnormalities, including neurogenic overactivity of the detrusor (hyporeflexia or areflexia), affect the performance of the external sphincter. In this sense, a study by Kabay  highlights how a 12-week treatment with percutaneous stimulation of the posterior tibial nerve, PTNS, produced a statistically significant improvement in LUTS and urodynamic parameters in PD patients. The parameters used in the study included urodynamic measurements before and after 12 weeks of treatment with PTNS; short questionnaire form (ICIQ-SF); and overactive bladder questionnaire (OAB-V8). The protocol used is the same, parameterised to fixed stimulation stimuli as described in the literature.
Contrary to motor disorders, many PD patients are not responders to levodopa treatment for LUTS, which is why non-invasive treatment with PTNS could be a proposal to all those PD patients whose other conservative therapies have failed to respond significantly.
As we know, the exact mechanism and effect of PTNS on the neurological bladder are not yet clear; the study by Finazzi-Agrò  reports the effect on the supraspinal centres reporting a significant increase in the magnitude of somatosensory evoked potentials to long latency recorded 24 h after the end of a PTNS programme session. This discovery could reflect a change in the processing mechanisms of sensory stimuli and suggests a possible reorganisation of cortical excitability after PTNS. Improvement, especially concerning the overactive bladder, is an encouraging result that suggests the stimulation of the posterior tibial nerve as a non-invasive treatment method in patients with the neurological bladder.
8.7 Bladder Catheterism
The suprapontine neurological bladder is the consequence of lesions in both cerebral hemispheres, particularly in the frontal lobes (multi-infarct encephalopathy, brain atrophy, tumours, brain traumas, hydrocephalus) or in the basal ganglia (Parkinson’s disease and multiple system atrophy).
Brain suffering causes a reduction in inhibitory control that is exercised under physiological conditions on the urination pontine centre; consequently an uncontrolled detrusor activity is established, defined as “neurogenic detrusor overactivity”. Patients are affected by non-inhibited detrusor contractions that cause an increase in voiding frequency, reduction in the ability to delay the voiding action after the appearance of the first stimulus (urgency) and an “urgency” incontinence. The post-voiding bladder residue, i.e. the amount of urine that remains in the bladder after urination, is absent or insignificant (less than 80 mL); diseases that most frequently involve this condition are cerebral thrombosis and haemorrhages, dementia (Alzheimer’s, Pick), brain tumours and hydrocephalus.
Urinary disorders in patients with Parkinson’s disease generally appear in late stages of the disease and are related to the depletion of dopaminergic neurons in the black substance and the subsequent reduction of striatal dopamine. Thus, secondary detrusor overactivity and reduced D1 mediated tonic inhibitory activity are determined. An alternative hypothesis is the presence of a neurotransmitter imbalance of neurons, with a facilitating action on the urination pontine centre, the ventral tegmental area that would cause pollakiuria (urination for low volumes of bladder filling), nocturia (repeated nocturnal urination) and urination urgency. In addition to detrusor overactivity, in Parkinson’s disease, there is also a delayed relaxation of the perineal musculature at the beginning of the voiding action (bradykinesia of the striatum external urethral sphincter) and a detrusor muscle contractility deficit, secondary to anti-Parkinsonian drug therapy, which can cause partial urinary retention.