Overactive bladder (OAB) treatment with sacral neuromodulation (SNM) is a device-based therapy delivering electrical stimulation to the sacral nerve. SNM is configurable for each patient with adjustable settings and multiple lead electrodes. Selection of initial stimulation settings (electrode configurations and amplitude) and subsequent programming changes are informed by a combination of visual motor, and patient-reported sensory response: patient preference and reported symptom relief. One common approach relies on patient-reported perception of the location and sensation elicited by stimulation on different electrode programs while increasing amplitude on each (e.g., vibration in vaginal or perianal region). Consistently recognizing and reporting differences in sensation and intensity across different settings and patients is limited without a straightforward way to quantify changes (e.g., in sensation onset, intensity). Growing evidence supports that sacral stimulation evoked electrical signals recorded from implanted SNM leads may add a useful tool to aid in programming [1, 2, 3]. Extending our ongoing characterization of sacral evoked responses (SERs), here we compare for the first time, the consistency of objectively measured SER thresholds (SERTs, lowest amplitude at which a SER can be measured) and subjective patient-reported sensory thresholds (STs, lowest amplitude at which sensation is perceived).  

Investigational device use. Limited by Federal (U.S.) law to investigational use. Not approved by FDA and not for sale in the U.S.

The PEER 2 study is an ongoing multi-center, prospective, clinical feasibility study. Subjects with OAB that met all inclusion and no exclusion criteria were implanted with a market-released tined SNM lead. Following lead implant, SER recordings were collected using the implanted SNM tined leads connected to an external investigational research system. SERs and STs were collected immediately post-operatively (PO) and at the end of the therapy evaluation period (Trial End, up to 14 days post-implant) across up to six different electrode configurations. Tested electrode configurations were bipolar stimulation pairs (e.g., configuration E3/E0 is stimulation using the most proximal electrode 3 and most distal electrode 0) with sensing across the remaining two electrodes (E1/E2).  In a subset of patients, at Trial End, a single stimulation/sensing configuration was repeated three additional times to assess consistency of ST and SERT measurement. Adverse device effects (ADEs) were collected as any event determined by the investigator to be related to the device, procedure, or therapy. Recordings were processed and analyzed to determine the lowest stimulation amplitudes associated with a detectable signal (SERT). Recordings were excluded from correlation and threshold consistency analysis if paired data (ST and SERT) were not available. Correlations were performed using MATLAB to evaluate the relationship between SERTs and STs.

Data collection at PO and at Trial End has been completed in 70 female OAB subjects with median (IQR) age of 66 (55 – 73) years and median (IQR) baseline symptoms of 6.0 (3.0 – 9.0) urgent leaks/day for urinary urge incontinence subjects (n=57) and 10.9 (9.7 – 14.8) voids/day for urinary frequency subjects (n=49). There were no ADEs related to the investigational device, while 4 ADEs were reported in 3 patients, 1 during therapy trial and 3 following implant of the commercial neurostimulator. Data from ongoing interim analyses continue to characterize and compare SERTs and STs in a growing number of subjects, confirming earlier findings. When grouped together across subjects and stimulation/sensing electrode configurations, lead-measured SERTs and patient-reported STs are correlated at PO (R=0.84, p<0.01, n=351 signals, 68 subjects) and Trial End timepoints (R=0.63, p<0.01, n=381 signals, in 70 subjects). As shown in Figure 1, SERTs are often detectable at lower stimulation amplitudes than STs and are reliably detected below maximum tolerable amplitudes (MTA). 
In a small subset of the study population (13 subjects), we compared the consistency across repetitions of subjective (ST) and objective (SERT) measures of response to stimulation. ST and SERT recordings were collected in 4 trials: one initial trial and three consecutive repeat trials. For each subject, sets of replicates were recorded within the same data collection session using a single stimulation/sensing configuration. Differences between each replicate and the initial measure were calculated and plotted in Figure 2. Differences of the 3 repeats were higher, lower or the same as the initial value. The differences for repeated measures from the initial measure show more variation for STs compared to SERTs (Figure 2). Repeated measurement of sensory threshold was consistent (no change) in 3/13 of subjects (23.1%), whereas repeated measurement of SERT was consistent in 10/13 subjects (69.2%). We evaluated the variation by comparing the range across replicates within each subject, expressed as a % of the initial measure. The median and interquartile range for ST was 16.7% (24.8) across subjects (n=13 subjects), compared to 0% (0) for repeated measurement of SERT (n=13 subjects).

As indicators of stimulation-elicited sacral nerve activation, both SERTs and STs can vary with differences in the relative electrode-nerve positioning. However, lead measured SERTs may offer advantages. SERTs are a direct measurement of physiological response to stimulation while STs are a patient’s perception secondary to nerve activation. Sensory responses are impacted by patient-specific factors influencing individual interpretation of the perceived onset, location, and description of stimulation-elicited sensation. Lead-detected SERs are a locally measured quantity reporting on stimulation-elicited electrical activity. As we have previously reported, different electrode configurations create slightly different stimulation fields, and therefore may have a different threshold to activate the nerve. Additionally, the different sensing configurations (wide, narrow, or interleaved relative to the stimulation configuration) may impact SERT detection. Here, we add an important characteristic of SNM lead-measured SERTs compared to patient-reported STs: SERTs exhibit high consistency/repeatability and lower variation across replicate measures compared to STs. This difference in precision underlies the observed variations in the relative amplitudes and correlations of SERTs and STs for subjects, timepoints, and configurations.

SERTs are reliably measurable from the same implanted SNM lead that delivers therapy, often at sub-sensory stimulation amplitudes. When recorded across multiple repeat measures, SERTs are more consistent compared to STs. SERTs as objective measures of stimulation-elicited nerve activation may offer potential advantages compared to existing subjective patient-reported measures for comparing and selecting programming settings.

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Goudelocke, C., et al. Neurourol Urodyn. 2024; 43 (S1: SUFU 2024 Abstracts); S58.

Continence 12S (2024) 101597
DOI: 10.1016/j.cont.2024.101597