Transcutaneous tibial nerve stimulation for the treatment of bladder storage symptoms in people with multiple sclerosis: Protocol of a single-arm feasibility study

Background

Neurogenic lower urinary tract dysfunction is defined by the International Continence Society (ICS) as “lower urinary tract symptoms (LUTSs) in the presence of a relevant neurological disease” (Gajewski et al., 2018). Storage symptoms associated with LUTS include frequency, urgency, nocturia, and/or incontinence; voiding symptoms resulting in hesitancy, slow stream, intermittency, dysuria, straining, terminal dripple, need to immediately re-void, splitting or spraying whereas post micturition symptoms include incomplete bladder emptying and/or post micturition dribble (Gajewski et al., 2018). The range and severity of neurogenic bladder symptoms depend on the location of the neurologic lesions (Li et al., 2016; Peter & Peter, 2012), with more pronounced symptoms in people with MS associated with lesions at the pontine micturition centre (PMC) leading to storage symptoms and or the supra sacral lesions resulting in both storage and voiding symptoms accompanied with an increased post-void residual (Haylen et al., 2010; McCombe et al., 2009; Panicker et al., 2015).

We recently undertook a systematic review and meta- analysis which demonstrated that LUTSs are prevalent in people with MS with a pooled prevalence of 68.41% using self-report measures and 63.95% using urodynamic studies. When considering types of LUTSs, urinary frequency was the predominant symptom followed by urgency with a pooled prevalence estimate of 73.45% and 63.87% respectively using self-report measures. Detrusor overactivity was found to be the most prevalent urodynamic symptom, with a pooled prevalence estimate of 42.9% followed by detrusor sphincter dyssynergia at 35.44% (Al Dandan et al., 2020). The high prevalence of urinary symptoms among people with MS is concerning as several studies have highlighted the negative consequences of urinary symptoms for quality of life (Browne et al., 2015; Finlayson et al., 2006; Nortvedt et al., 2001; Vitkova et al., 2014). Studies have shown that urinary incontinence is considered as one of the worst morbidities associated with MS (Fowler et al., 2009; Nakipoglu et al., 2009). Urinary symptoms including loss of urine that results in fear of leaking in public is considered as a barrier to engaging in physical activities among people with MS (Kayes et al., 2011). Furthermore, an increased risk of mortality and an aggravation of MS symptoms following an episode of urinary tract infection (UTIs) has been reported (Abrams et al., 2017). Timely diagnosis and proper management are of utmost importance in maintaining good quality of life among people with MS and urinary symptoms.

Current therapeutic interventions for storage symptoms include pharmacologic therapy, behavioural interventions, pelvic floor muscle training (PFMT), and/ or neuromodulation. Pharmacologic interventions such as the use of anticholinergic medication are considered a first-line treatment for neurogenic bladder population (Chapple et al., 2008; Tornic & Panicker, 2018). Anticholinergic short-term efficacy has been reported in previous studies, however, limited long-term efficacy due to side effects and lack of tolerance was reported (de Seze et al., 2011; Fowler et al., 2009; Li et al., 2016; Panicker et al., 2015; Stöhrer et al., 2009; Tornic & Panicker, 2018; Valles-Antuna et al., 2017). The reported side effects include; gastrointestinal tract disorders, central nervous system particularly worsening in cognition and deterioration in memory, dry mouth, impact on complete bladder emptying and increase cost.

A systematic review identified very few high quality studies of non-pharmacological interventions such as behavioural interventions including management of fluid intake, bladder retraining and scheduled voiding among a neurogenic population including people with MS (Panicker et al., 2015). Combined pelvic floor muscle training (PFMT) therapy with electromyography (EMG) biofeedback and intravaginal neuromuscular electrical stimulation (NMES) reduced urinary symptoms including number of leaks and pad test among 30 females with MS when compared to PFMT alone or PFMT and EMG biofeedback (McClurg et al., 2006). A recent systematic review showed that PFMT alone or in conjunction with other interventions among people with MS is also considered to be effective and classified as a first-line treatment approach (Tornic & Panicker, 2018). Of concern, across numerous studies with non-neurological populations adherence to PFMT has been shown to be the main factor influencing the improvement of urinary symptoms (Bø et al., 2005; Prasad et al., 2019; Sacomori et al., 2019). One study showed some barriers to adherence among postpartum women included forgetfulness, lack of time, and chores related to childcare (Sacomori et al., 2019). On the other hand, another study showed that using simple reminder methods could improve the adherence rate of PFMT and consequently improve urinary symptoms (Prasad et al., 2019). Further studies are needed to assess adherence to PFMT among people with MS and urinary symptoms and the influence of adherence on urinary symptoms in MS.

The European Association of Urology (EAU), American Urology Association (AUA), and UK National Institute for Care and Clinical Excellence (NICE) recommend combined therapeutic interventions of PFMT and behavioural intervention for non-neurogenic OAB symptoms (Nambiar & Lucas, 2014) with no clear recommendations for neurogenic bladder symptoms. Intra-detrusor Onabotulinum toxin A (BoNT-A) injection is the most effective therapeutic intervention that classified as a second-line intervention for neurogenic bladder according to EAU guidelines (Nambiar & Lucas, 2014; Tornic & Panicker, 2018). Despite the reported efficacy of this intervention among neurogenic population and particularly people with MS in improving subjective urinary symptoms and urodynamic parameters (Cruz et al., 2011; Denys et al., 2017; Fowler et al., 2009; Kalsi et al., 2007; McCombe et al., 2009; Woodwar, 2004), several adverse events and limitations have been reported including; generalised muscle weakness, the need for repeated injections, increased risk of urinary tract infections (UTIs), increased risk of post-void residual (PVR) due to decline in bladder contractility resulting in the need of clean intermittent catheterization (CIC) afterwards, and rare but severe side effects were also reported such as respiratory problems (Fowler et al., 2009; Groen et al., 2016; Kalsi et al., 2007; Panicker & Fowler, 2015; Stöhrer et al., 2009; Tornic & Panicker, 2018). Although the literature reported the required dosage for BoNT-A injection is 100 unit (Mehnert et al., 2010), the needed dosage for each treatment session is still debatable (Sahai et al., 2010).

Neuromodulation is another available intervention for neurogenic storage symptoms among people with MS. This intervention may include non-invasive, semi-invasive or an invasive surgical procedure. Non-invasive neuromodulation techniques include electrical stimulation of peripheral nerves such as pudendal nerve, dorsal genital nerves, and/ or tibial nerve. Although some studies showed a significant improvement of urinary symptoms using pudendal nerve or dorsal genital nerves among non-neurogenic OAB population, there is a need for further large high quality studies (Jaqua & Powell, 2017; Janssen et al., 2017), with a lack of clear efficacy among neurogenic bladder populations.

Tibial nerve stimulation proximal to medial malleolus using adhesive cutaneous electrodes is another form of non-invasive neuromodulation for bladder storage management called transcutaneous tibial nerve stimulation (TTNS). Percutaneous Tibial Nerve Stimulation (PTNS) is a semi-invasive neuromodulation in which needle electrode is used to stimulate the tibial nerve fibres. Therefore, TTNS could be an alternative intervention among people with MS. Recent reviews have shown that tibial nerve stimulation may be effective in managing storage symptoms in people with non-neurogenic and neurogenic bladder with future high quality studies needed among people with MS (Aharony et al., 2017; Panicker et al., 2015; Schneider et al., 2015; Tornic & Panicker, 2018). The tibial nerve is a mixed nerve containing sensory and motor fibres of L4-S3, and it originates from the same segments of the spinal cord as the innervation to the bladder, pelvic floor, and rectum. The exact mechanism through which tibial nerve neuromodulation potentially treats bladder storage related symptoms is not yet fully understood (Arya & Weissbart, 2017; Gaziev et al., 2013; Joussain & Denys, 2015; Valles-Antuna et al., 2017). However, it is believed that stimulation of the tibial nerve with low-frequency pulses at tolerable intensity can produce inhibition of the spinothalamic neurons within the spinal cord, reduce firing input to the pontine micturition centres (PMC), which in turn inhibits the information facilitated by those nerves to the bladder (Chancellor & Chartier-Kastler, 2000; Choudhary et al., 2016; de Groat, 1997; Devane et al., 2015; Zecca et al., 2016). Neuromodulation may also have supra-spinal effects which has been investigated in human studies by studying somatosensory evoked potentials before and after Percutaneous tibial nerve stimulation (PTNS) and sacral neuromodulation (SNM). The results showed alterations in somatosensory evoked potential (Finazzi-Agrò et al., 2009; Valles-Antuna et al., 2017). This means that stimulation at the tibial nerve, results in modifications of synaptic efficiency through the somatosensory pathway providing information on the function of somatosensory cortical structures at the spino-thalamic level. Although people with MS might have scattered lesions at spinal cord level, some studies showed some promising evidence from tibial nerve stimulation intervention for bladder control in MS. Further studies are needed to determine the correlation between spinal cord lesions and tibial nerve stimulation intervention among people with MS and bladder storage symptoms.

Our review of the literature revealed few studies investigating TTNS among neurogenic bladder (Amarenco et al., 2003; Monteiro et al., 2014; Perissinotto et al., 2015; Valles-Antuna et al., 2017). Specific to people with MS, two experimental studies were identified (de Seze et al., 2011; Seth et al., 2018). In the uncontrolled experimental study by de Seze et al. (2011); the authors recruited 70 people with MS and OAB. All participants were asked to apply TTNS daily for 20 minutes for 12 weeks. This study found significant improvements in urinary related symptoms of urgency, frequency, and nocturia in 82.6% at the end of week 4, and 83.3% improvement at the end of week 12. Urodynamic studies showed significant improvement by increasing maximum cystometric capacity and reflex volume in about half of the participants (51.2%.).

A second study was a randomised pilot study assessing the safety, acceptability and pilot efficacy of transcutaneous low-frequency TTNS using self-applicating ambulatory skin-adhering device stimulating the tibial nerve called geko^TM at a frequency of 1 Hz. The study compared two different protocol of TTNS 30 min daily vs. 30 min weekly, for 12 weeks between 24 MS participants with OAB to 24 participants with idiopathic OAB. TTNS was shown to be safe, acceptable and significant improvements in urinary symptoms including OAB were reported for both groups (Seth et al., 2015; Seth et al., 2018). The electrical stimulation parameters for both groups were at 27 mA current, with 1 Hz current frequency and pulse width was between 70 and 560 µs and was consecutively increased depending upon the maximum tolerable sensory and best sensory-motor response.

The potential efficacy of TTNS among people with MS with urinary symptoms is based on a small number of studies with a large number of authors identifying the absence of high-quality evidence relating to the electrical stimulation parameters, frequency of treatment per week, and total number of sessions (Booth et al., 2018; Burton et al., 2012; Schneider et al., 2015; Slovak et al., 2015; Tudor et al., 2020; Zecca et al., 2016).

Randomised controlled trials are required to provide a robust evidence-base for using TTNS for neurogenic bladder storage related symptoms in MS. Therefore, there is a need to assess the feasibility of TTNS in storage symptoms among people with MS using, widely available and affordable device, the transcutaneous electrical nerve stimulation (TENS) unit to proceed with a definitive randomised trial.

Methods

The CONSORT extension for pilot and feasibility studies will be followed to standardise the conduct and reporting of the study (Eldridge et al., 2016). Ethical approval was obtained from the Faculty of Education and Health Sciences Research Ethics Committee at the University of Limerick [2020_06_07_EHS]. This study was registered with ClinicalTrials.gov on 27^th August 2020 (NCT04528784). The trial registration platform will be updated if any changes are made to the trial.

Conclusion

To the authors’ knowledge, no feasibility studies have been conducted to evaluate the feasibility of TTNS application for managing storage bladder symptoms in MS. It is anticipated that assessing the feasibility for the application of TTNS among people with MS will contribute to proceed with a definitive randomised trial.

Data availability