Future advancements in neuromodulation

Author: Prof. Marcio Averbeck, Board Member, ESFU Head of Neuro-Urology, Moinhos de  Vento Hospital, Porto Alegre (BR)

OAB is defined by the International Continence Society (ICS) as urinary urgency, usually accompanied by frequency and nocturia, with or without urgency urinary incontinence, in the absence of a urinary tract infection or other obvious pathology. One in six adults in Europe and the United States suffer from OAB, a frequent and disabling disorder. Neuromodulation techniques are advised as a third-line therapy, following the failure of behavioural and pharmacological therapies. Fundamental technological advances in sacral neuromodulation (SNM) have been implemented over the past few years, including implantable pulse generators with longer half-lives, rechargeable and MRI-compatible devices. However, the advances do not stop there. Other innovative and promising technologies are currently being developed specifically for patients with refractory LUTD.

Implantable Tibial Nerve Stimulators (ITNS) 

Percutaneous tibial nerve stimulation (PTNS) is currently recommended by international guidelines as an alternative for refractory OAB [5], but over 40% of patients receiving maintenance stop PTNS therapy due to logistic reasons and physical strain during a 6-year follow-up. This inherent limitation led to further developments. Three implantable tibial nerve stimulator (ITNS) systems are available as a result of rapid technological advancement: the Bioness StimRouter®, the Revi® and the eCoin® device. Clinical trials are now being conducted to test other ITNS technologies; findings are not yet available.

Bioness Stimrouter 

An implanted lead with an integrated receiver, an anchor, and three electrode contacts makes up the Bioness Stimrouter device. The implant is done under local anaesthesia and guided by ultrasound (Fig. 1). The electrode patch and external pulse transmitter provide wireless transdermal stimulation energy, which is captured by the lead. The device's programmes are changed and usage is monitored via a patient programmer. This device has been initially studied in individuals with chronic pain. Ninety-four patients were randomised to either the active treatment group (45) or the control group (49). Three months after treatment randomisation, patients receiving active stimulation had a statistically significant greater response rate (38% vs. 10% in the Control group) (p = 0.0048). Treatment group experienced a mean pain reduction of 27.2% from baseline to month 3, while the control group only experienced a 2.3% reduction (p < 0.0001). Following its CE Mark in February 2014 for the treatment of chronic pain of peripheral nerve origin and as an adjunct to other non-drug therapeutic options, in February 2019 the StimRouter received CE Mark Approval for the treatment of overactive bladder (OAB) across Europe. Clinical trials for this indication are ongoing. Outcomes in patients with multiple sclerosis have been recently published.

eCoin 

The eCoin is a self-contained stimulator that comes in a single implanted canister that houses the circular electrode and a power supply. This stimulator system includes cyclic therapy, which is administered every three days for the first eighteen weeks, then chronically every four days after that. Each therapy session lasts 30 minutes. It uses a fixed 20 Hz frequency and 0.2 ms pulse width, with an amplitude between 0.5 and 15 mA. The power supply for this system lasts for 36 months. Patients with refractory wet OAB (n = 137) participated in a prospective, multicentre, single-arm clinical trial aimed to assess the efficacy of eCoin ITNS therapy. Along with the Patient Global Impression of Improvement, the overactive bladder questionnaire, and a customised Likert scale measuring subject satisfaction, a 3-day voiding diary was registered. The percentage of participants who reduced the number of urgency urinary incontinence (UUI) episodes of by at least 50% from baseline was taken as the primary outcome measure. Ninety-six weeks of treatment were finished by 72 participants. On a three-day diary, 78% (95% CI: 67% - 87%) reported at least a 50% reduction in UUI episodes, 48% (95% CI: 36%-60%) reported at least a 75% reduction, and 22% (95% CI: 13%-33%) reported being dry. 91.3% of OAB patients stopped taking oral medicines. During this extension phase, no significant or unexpected adverse events were reported.

Revi System 

The Revi System is the new name for the ITNS that was originally described under the name RENOVA iStim. The Revi ITNS consists of a single implant with an internal receiver. The implant communicates with an external power source to enable stimulation and control of stimulation parameters. Frequency, pulse width, and polarity shift are among the modulable parameters. An external anklet is utilised to apply treatment; in clinical studies, it has been used once daily for 30 minutes at a time for stimulation sessions. Additionally, the device may record and evaluate treatments via a cloud-based system for the purpose of oversight of patient device use. An open-label, single-arm, prospective, multicentre, pivotal study assessed the Revi ITNS efficacy and safety in adult females with wet OAB. The proportion of patients who responded to therapy ( ≥ 50% reduction in the number of UUI episodes) and the frequency of adverse events from the time of implantation to one year after activation were the main outcome measures for efficacy and safety. Altogether, 151 subjects underwent the procedure (mean age: 58.8 years); 140 and 144 of them finished the 6- and 12-month visits, respectively. In an intent-to-treat analysis, 76.4% and 78.4% of participants were classified as responders at six and twelve months after activation. Eighty-two percent of the 139 subjects whose 12-month bladder diaries were completed were responders, fifty percent were categorised as "dry", and ninety-three percent of participants said their symptoms had improved. There were no serious adverse events associated with the surgery or device. 

What does the future hold? Is there room for pudendal nerve stimulation? Adaptive pudendal nerve stimulation? 

A small randomised clinical trial compared SNM and pudendal nerve stimulation (PNS) in patients with BPS/IC (n = 22). Patients received a tined-lead SNM electrode placed at S3 and a second electrode implanted at the pudendal nerve via a posterior approach. Each one was tested for 7 days, and the best lead was implanted to a pulse generator. Subjects were followed at 1, 3 and 6 months. PNS was the superior in 77% of cases, and SNM in 24%. For PNS and SNM, respectively, the overall symptom improvement was 59% and 44% (p = 0.05). After six months, mean voided volume increased 95% and 21%, and voids improved by 41% and 33%, in PNS and SNM, respectively. Adverse events were negligible. Another study suggested that PNS could be a reasonable alternative in complex patients refractory to other therapies, including SNM. Despite promising outcomes, further studies are still needed to assess which patient groups may benefit the most from PNS versus SNM. 

More recently, De Wachter et al. presented preliminary data from the AURA-2 trial (NCT05241379) during the Society of Urodynamics, Female Pelvic Medicine & Urogenital Reconstruction (SUFU) annual meeting in Fort Lauderdale, Florida. [13, 14] This study assessed the safety and feasibility of a new device called Amber-UI® therapy, an implantable, “adaptive” pudendal neuromodulation system for the treatment of patients with urinary incontinence (UI). Acute stimulation provided by this device showed effects on both sphincter muscle (detected by electromyography measurements) and on suppression of detrusor overactivity leading to increased mean cystometric capacity. This effect led to improvements in patients with mixed UI. The device’s adaptive algorithms were able to detect relevant physiological biomarkers of pelvic neuromuscular activity in real-time in vivo. Interim data showed that 80% (4 of 5) of evaluable women experienced a complete resolution of mixed UI at 6-month follow-up. Future well-designed trials, with adequate number of patients included, are awaited to demonstrate whether these encouraging results will be confirmed.