Neurourology and urodynamics · 2025
Царская нейромодия для нейрогенного Нижнего Уринарного тракта, Боул и Сексуальная дисфункция у пациентов с множественным склерозом: экспериментальное испытание.
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Kobberø Hanne, Krhut Jan, Zvara Peter, Pedersen Torben Brøchner, Fode Mikkel, Nielsen Helle Hvilsted, Poulsen Mads Hvid
Аннотация
АИСЮ: Мы представляем результаты two- Экспериментальное исследование с применением огнестрельного оружия для оценки целесообразности проведения двухзвукового выборочного контролируемого испытания (РКТ) с целью оценки эффективности нейромодуляции (СНМ) у пациентов с множественным склерозом (МС), страдающих нейрогеническим расстройством нижних мочевых путей (НЛУТД). МЕТОДЫ: Учитываемые темы с рефрактным NLUTD и EDS < 5 Прошла стадию испытания SNM. Те, кто показывают больше, чем 50% - усовершенствование переменных мочевого пузыря, получение имплантируемых импульсных генераторов (ИПГ) и произвольное включение либо в группу обработки (IPG OFF), либо в группу подделки (IG OFF) 1 месяц. В течение второго месяца все пациенты имели IPG OP до конца испытания. Основными конечными точками являются практическая осуществимость экспериментального процесса, потенциал набора персонала и доля респондентов на завершающем этапе теста SNM. Вторым моментом была безопасность. Были также зарегистрированы изменения в ключевых переменных дневника мочевого пузыря и сообщаемых пациентами результатах. Результаты: Thirty-two пациентов проверяли, 17 имели право на получение и 13 были включены в этап испытаний SNM. Eleven были признаны ответителями и имплантированы IPG. Впоследствии six :: пациенты были случайными для лечебной группы и five за фиктивную группу. Сообщений о каких-либо серьезных негативных событиях не поступало. На этапе вмешательства были отмечены как объективные, так и субъективные улучшения в группе, занимающейся лечением, в то время как симптомы в фальшивой группе в основном остались неизменными. После завершения обучения, six пациенты сообщили, что они полностью удовлетворены, three были в основном удовлетворены, и two были равнодушны к лечению. ВЫВОДЫ: Этот экспериментальный эксперимент продемонстрировал возможность оценки безопасности и эффективности SNM у пациентов, страдающих НРЖ, с двойным затвором. ТРИБАЛЬНАЯ РЕГИСТРАЦИЯ: Клинические производства.gov NCT05380856.
Оригинал публикации
Sacral Neuromodulation for Neurogenic Lower Urinary Tract, Bowel and Sexual Dysfunction in Patients With Multiple Sclerosis: A Pilot Trial.
AIMS: We present results of a two-arm pilot study assessing the feasibility of conducting a double-blind randomized controlled trial (RCT) to evaluate the efficacy of sacral neuromodulation (SNM) in patients with multiple sclerosis (MS) suffering from neurogenic lower urinary tract dysfunction (NLUTD).
METHODS: Eligible subjects with refractory NLUTD and EDSS < 5 underwent SNM test phase. Those showing more than a 50% improvement of bladder variables, received implantable pulse generators (IPG) and were randomized to either treatment group (IPG ON) or to sham group (IPG OFF) for 1 month. During second month, all patients had the IPG ON until the end of the trial. The primary endpoints were trial feasibility, recruitment potential, and response rate at the end of SNM test phase. Secondary endpoint was safety. Changes in key bladder diary-derived variables and patient reported outcomes were recorded as well.
RESULTS: Thirty-two patients were screened, 17 were eligible and 13 were included in the SNM test phase. Eleven were considered responders and were implanted with IPG. Subsequently, six patients were randomized to the treatment group and five to the sham group. No serious adverse events were reported. In the intervention phase, both objective and subjective improvements were seen in the treatment group, while the symptoms in the sham group remained mostly unchanged. At study completion, six patients reported being completely satisfied, three were mostly satisfied, and two were indifferent to the treatment.
CONCLUSIONS: This pilot trial demonstrated feasibility of double-blind RCT assessing safety and efficacy of SNM in MS patients.
TRIAL REGISTRATION: ClinicalTrials.gov NCT05380856.
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Abbreviations
Bladder Diary
Body Mass Index
Clean Intermittent Catheterization
Expanded Disability Status Scale
European Quality of Life 5 Dimensions Questionnaire
Global Assessment Scale
International Consultation on Incontinence Questionnaires Anal Incontinence Symptoms and Quality of Life
International Consultation on Incontinence Questionnaires about Female Lower Urinary Tract Symptoms
International Consultation on Incontinence Questionnaires about Female Sexual Matters Associated with Lower urinary Tract Symptoms
International Consultation on Incontinence Questionnaires about Male Lower Urinary Tract Symptoms
International Consultation on Incontinence Questionnaires about Male Sexual Matters Associated with Lower urinary Tract Symptoms
Implantable Pulse Generator
Interquartile Range
Milliampere
Multiple Sclerosis
Neurogenic Lower Urinary Tract Dysfunction
Patient Related Outcome Measure
Post‐void Residuals
Pad Weight Test
Maximum Urine Flow Rate, mL/s
Quality of Life
Randomized Controlled Trial
Relapsing‐Remitting Multiple Sclerosis
Sham Group
Sacral Neuromodulation
Treatment Group
Volt
Introduction
Multiple sclerosis (MS) is a chronic inflammatory, neurodegenerative and progressive disorder causing demyelination and axonal loss in the central nervous system [ 1 ]. The symptomatology includes neurogenic lower urinary tract dysfunction (NLUTD) as well as bowel and sexual dysfunctions [ 2 ].
The incidence of urinary symptoms increases with disease duration and involvement of the motor system [ 1 ]. After ten years with MS, nearly all patients experience urinary symptoms, affecting the storage and/or voiding phase with increased urinary frequency and urgency as the most bothersome symptoms. Both neurogenic bowel and sexual dysfunction affect around 50% of MS patients [ 2 ].
According to European and US guidelines, the treatment options for NLUTD encompass behavioral therapy, various catheterization methods, oral drugs and bladder injections with Onabotulinum Toxin A. For more severe cases, surgical interventions such as bladder augmentation may be considered [ 3 , 4 ].
Since 2020, SNM devices have become fully MRI‐compatible, making SNM an attractive option for MS patients, who require regular MRI monitoring as part of their follow‐up. However, no dedicated randomized controlled trials (RCTs) have been conducted specifically for this patient group [ 5 , 6 ].
The aim of this pilot trial is to investigate the feasibility of conducting a RCT by assessing recruitment potential, response rate, protocol adherence, and obtaining key safety and efficacy data required for planning of a future RCT in MS patients.
Materials and Methods
The trial was conducted in accordance with the principles of the Declaration of Helsinki, the World Medical Association, and the CONSORT 2010 statement [ 7 ]. The study protocol was approved by the Ethical Committee on Health Research Ethics for Southern Denmark No. 77525. All participants provided written informed consent. The trial was registered on ClinicalTrials. gov NCT05380856 .
Participants
We enrolled adult MS patients with NLUTD, i.e. urgency frequency and/or incontinence or chronic urinary retention. These patients were refractory to conservative treatment such as lifestyle modifications, antimuscarinics and/or beta‐3 agonists.
Inclusion criteria were: Diagnosis of MS according to the revised McDonald Criteria 2017 [ 8 ], Expanded Disability Status Scale (EDSS) less than 5, no progression of neurological disease within 6 months, and ability to handle the SNM control unit. Exclusion criteria included urological, bowel or gynecological pathology caused by diseases other than MS, bladder injections with OnabotulinumToxin A within 6 months, and percutaneous tibial nerve stimulation within 2 months before inclusion.
Study Design
This was a single‐center randomized two‐arm parallel‐group, non‐blinded pilot trial. Eligible subjects underwent a complete neuro‐urological investigation including a 3‐day bladder diary (BD), questionnaires of patient related outcome measures (PROMs), uroflowmetry, post‐void residual measurement (PVR), cystoscopy and imaging of the kidneys to assess baseline characteristics ( Baseline ). The patients were categorized into three subgroups of NLUTD, according to their predominant symptoms (urgency/urgency incontinence, chronic urinary retention, combination of both).
After baseline assessments, enrolled patients underwent implantation of the tined lead electrode using the standardized electrode placement technique [ 9 ]. At the subsequent programming, a subsensory threshold of stimulation was chosen. After 4 weeks of SNM testing ( End of Test Phase), the treatment response was evaluated by 3‐day BD and PROMs. Responders were defined as patients who achieved a 50% or greater improvement in key BD‐derived variables compared to Baseline [ 10 ].
Responders were implanted with implantable pulse generator (IPG). All patients, but one, were implanted with non‐rechargeable InterStim II, while one patient had the InterStim Micro rechargeable IPG (Medtronic Inc. Minneapolis, MN, USA). Subsequently, patients were non‐blindly randomized in a 1:1 ratio to either the treatment or sham group, using a computer‐generated list. Patients assigned to the treatment group were stimulated at 0.1–0.2 V below the sensory threshold for the next 4 weeks, while patients assigned to the sham group were kept without stimulation for the same duration. At the End of Intervention Phase , all patients were assessed using a 3‐day BD and PROMs.
Subsequently, the patients in the sham group had their stimulation activated and all the subjects were stimulated for additional 4 weeks, at which point the trial was concluded ( End of Trial ). The final evaluation was performed with 3‐day bladder diaries, PROMs, global assessment scale (GAS), uroflowmetry with maximum urine flow rate (Qmax), and post‐void residual (PVR).
The trial flow is depicted in Figure 1 .
Overview of the Trial Flow. Schematic summary of the study design. The columns describe the phases of the trial in chronological order (from left to right). ICIQ‐M/FLUTS: International Consultation on Incontinence Questionnaires about Male/Female Lower Urinary Tract Symptoms. ICIQ‐M/FLUTSsex: International Consultation on Incontinence Questionnaires about Male/Female Sexual Matters Associated with Lower urinary Tract Symptoms. EQ‐5D‐5L, European Quality of Life 5 Dimensions Questionnaire; GAS, Global Assessment Scale.
Study Assessments
Three‐day BD was recorded before each of the study timepoints. Numbers of voids, voided volume, numbers of urge urinary incontinence episodes, and pad weight test (PWT) were recorded in patients with spontaneous voiding and leading symptom of urgency/urgency incontinence, while numbers of clean intermittent catheterization (CIC) episodes and catheterized volume were recorded in patients with chronic urinary retention. All above mentioned variables were recorded in patients with both symptoms [ 10 ].
As PROMs, the validated Danish language International Consultation on Incontinence Questionnaires about Male Lower Urinary Tract Symptoms (ICIQ‐MLUTS) [ 11 ], Male Sexual Matters Associated with Lower urinary Tract Symptoms (ICIQ‐MLUTSsex) [ 12 ], Female Lower Urinary Tract Symptoms (ICIQ‐FLUTS) [ 13 ], Female Sexual Matters Associated with Lower urinary Tract Symptoms (ICIQ‐FLUTSsex) [ 14 ], and Anal Incontinence Symptoms and Quality of Life (ICIQ‐Bowel) [ 15 ] were used. In all questionnaires, higher scores signify higher symptom severity and higher impact on the quality of life.
To evaluate the impact of treatment on general health‐related quality of life (QoL), the European Quality of Life 5 Dimensions questionnaire (EQ‐5D‐5L) [ 16 ] was employed. A higher EQ‐5D‐5L index, signifies better QoL.
Additionally, GAS was used to assess patient satisfaction with the treatment. GAS is a 5‐point Likert scale ranging from complete dissatisfaction to completely satisfaction with the treatment.
Serious adverse events were monitored continuously according to MDCG 2020‐10/2 Clinical Investigation Summary Safety Report Form v1.0 [ 17 ].
We also monitored the stimulation parameters.
Endpoints
Primary endpoints were recruitment potential (numbers of patients eligible/numbers of patients screened in the trial), adherence to the protocol, and proportion of responders defined as more than a 50% improvement of key bladder variables at the End of Test Phase compared to Baseline.
Secondary endpoint was safety. In addition, we assessed changes in key BD variables, PROMs, patient satisfaction and QoL.
Statistical Analysis
Descriptive statistics to measure the central tendency was conducted using R version 4.3.3 (2024‐02‐29) software. The values are reported as median with range (min. – max.) or median with interquartile range (IQR). Given the low number of participants, further statistical analyses of the efficacy outcomes was not feasible.
Results
Patients, Study Feasibility, Recruitment Potential and Protocol Adherence
Between September 2021 to June 2023, 32 individuals were screened for participation. Of these, 17 (17/32) subjects were eligible for the study. Four subjects declined to participate. Thirteen patients met the inclusion criteria, provided consent, and were enrolled in the trial (Figure 2 ).
Consolidated Standards of Reporting Trials (CONSORT) diagram of the trial. IPG, Implantable Pulse Generator; NLUTD, Neurogenic Lower Urinary Tract Dysfunction.
Among the participants, 10 were females. The median age was 53 (min. 44–max. 62) years. All but one patient had relapsing/remitting MS with a median EDSS of 4.0 (min. 2.5–max. 4.5) (Table 1 ).
Table 1 Demographic and clinical characteristics of the study population. ID Sex Age (Years) MS type Duration of MS (Years) EDSS BMI NLUTD Allocation 1 Female 61 SPMS 15 2.5 30.9 Urgency/Urgency Incontinence TG 2 Female 62 RRMS 38 4.0 21.9 Urgency/Urgency Incontinence TG 3 Female 53 RRMS 15 4.0 30.9 Urgency/Urgency Incontinence TG 4 Female 49 RRMS 14 4.0 23.7 Urgency/Urgency Incontinence TG 5 Female 44 RRMS 16 4.5 25.7 Urgency/Urgency Incontinence SG 6 Female 59 RRMS 14 2.5 38.1 Chronic Urinary Retention SG 7 Female 59 RRMS 31 4.5 26.2 Chronic Urinary Retention TG 8 Female 45 RRMS 13 4.0 23.8 Combination SG 9 Female 48 RRMS 23 4.5 24.7 Combination SG 10 Female 58 RRMS 10 4.5 25.3 Combination TG 11 Male 51 RRMS 13 3.5 32.4 Combination SG Abbreviations: BMI, Body Mass Index; EDSS, Expanded Disability Status Scale; MS, Multiple Sclerosis; NLUTD, Neurogenic lower urinary tract dysfunction; RRMS, Relapsing‐Remitting Multiple Sclerosis¨; SG, Sham Group; SPMS, Secondary Progressive Multiple Sclerosis; TG, Treatment Group.
Demographic and clinical characteristics of the study population.
Abbreviations: BMI, Body Mass Index; EDSS, Expanded Disability Status Scale; MS, Multiple Sclerosis; NLUTD, Neurogenic lower urinary tract dysfunction; RRMS, Relapsing‐Remitting Multiple Sclerosis¨; SG, Sham Group; SPMS, Secondary Progressive Multiple Sclerosis; TG, Treatment Group.
At the End of Test Phase, 11 (11/13) patients (Five with urgency/urgency incontinence, 2 with chronic urinary retention, and 4 with a combination) were responders and subsequently were randomized into either treatment group (6 patients) or sham group (5 patients). Two patients were excluded; one male due to technical problems with the external stimulator and one female who did not respond to the treatment (Table 1 ).
All randomized patients attended the study visits, with no dropouts. All participants were able to record 3‐day BD and complete all questionnaires. Several patients were unable to complete the PWT during the trial (Table 2 ).
Table 2 Bladder diary‐derived variables in individuals throughout the trial period*. ID Baseline End of Test Phase End of intervention phase End of trial No. voids Blad Vol. ml No. CIC Vol. CICml No. leaks/day PWT No. voids Blad Vol. ml No. CIC Vol. CIC ml No. leaks/day PWT No. voids Blad Vol. ml No. CIC Vol. CIC ml No. leaks/day PWT No. voids Blad Vol. ml No. CIC Vol. CIC ml No. leaks/day PWT
URGENCY
1
8 152 NAN NA 3.7 UK 6 224 NA NA 0 0 9 183 NA NA 1 UK 9 200 NA NA UK UK
2
9 139 NA NA 1.7 66.5 10 174 NA NA 0 0 8 175 NA NA 0 0 10 185 NA NA 0 0
3
12 163 NA NA UK UK 8 195 NA NA 0 0 8 205 NA NA 0 0 9 195 NA NA 0 0
4
14 300 NA NA 1 UK 9 304 NA NA 0 0 14 215 NA NA 0 0 9 248 NA NA 0 0
5
9 248 NA NA 5.3 9 9 255 NA NA 0 0 6 343 NA NA 0 0 9 302 NA NA 0 0
RETENTION
6
NA NA 11 82 NA NA NA NA 9 139 NA NA NA NA 11 113 NA NA NA NA 8 110 NA NA
7
NA NA 12 220 NA NA NA NA 6 280 NA NA 1 *
67 *
4 314 NA NA 1 *
67 *
6 282 NA NA
COMBINATION
8
10 132 10 148 1.6 4 10 195 5 108 1.6 9.5 12 167 8 119 1.6 18 10 208 5 101 2.3 UK
9
22 102 2 208 0 0 10 144 2 333 0 0 15 151 2 267 0 0 14 127 2 236 0 0
10
9 141 7 101 3.3 158 7 294 6 54 1.3 36 10 148 7 114 1.3 19 9 187 2 80 2.5 36.5
11
15 127 2 174 1.5 UK 9 171 0 0 0 0 10 164 0 0 0 0 13 165 0 0 0 0
Note: Numbers represent mean values. Dark grey cells: IPG ON. Light grey cells: IPG OFF. Abbreviations: Blad Vol., Bladder Volume; CIC, Clean Intermittent Catheterization; PWT, Pad Weight Test; UK, Unkown. * Spontaneous voiding in retention group.
Bladder diary‐derived variables in individuals throughout the trial period*.
Note: Numbers represent mean values.
Dark grey cells: IPG ON.
Light grey cells: IPG OFF.
Abbreviations: Blad Vol., Bladder Volume; CIC, Clean Intermittent Catheterization; PWT, Pad Weight Test; UK, Unkown.
Spontaneous voiding in retention group.
Safety
The treatment was well tolerated. Aside from postoperative pain, which was managed with paracetamol and nonsteroidal anti‐inflammatory drugs, no treatment‐related or serious adverse events were reported during the trial.
At the End of the Test Phase, the device was easily removed without complication in both non‐responders, and their bladder condition returned to the pretreatment level.
C hanges in BD‐Derived Variables
At the End of Intervention Phase, 5 patients (5/6) in the treatment group and 1 patient (1/5) in the sham group maintained a 50% improvement in BD‐derived variables.
At the End of Trial, 8 of the 11 responders maintained a 50% improvement in BD‐derived variables. The most notable improvements were observed in numbers of urge urinary incontinence episodes among patients with symptoms of urgency/urgency incontinence and in the numbers of CIC in the combination symptoms subgroup (Table 2 ).
Changes in Uroflowmetry and PVR
Uroflowmetry including Qmax and PVR were assessed at Baseline and at the End of Trial. Nine (9/11) patients voided spontaneously throughout the trial. The median voided volume increased from 203 mL (IQR: 188; 270) to 238 mL (IQR: 180; 431). Similarly, both Qmax and PVR increased with a median from 19 mL/sec (IQR: 11; 22) to 25 mL/sec (IQR: 20; 34) and the median PVR increased from 55 mL (IQR: 33; 110) to 131 mL (IQR: 69; 164).
Changes in PROMs
Significant reduction in ICIQ‐FLUTS scores was observed from a median 19.0 (IQR: 16; 23) at Baseline to the 9.5 (IQR: 7; 12) at the End of the Test Phase.
At the End of Intervention Phase, the ICIQ‐FLUTS score remained stable in the treatment group with a median change of ‐1 (IQR: −2; −1), whereas the sham group experienced a substantial increase of 9 (IQR: 8; 11) compared to End of Test Phase.
By the End of Trial, ICIQ‐FLUTS scores in the patients assigned to the sham group showed improvement to the level of End of the Test Phase. Patients in the treatment group maintained similar ICIQ‐FLUTS scores (Table 3 ).
Table 3 Changes in bladder volume, ICIQ‐FLUTS, ICIQ‐Bowel, ICIQ‐FLUTSsex and quality of life throughout the trial period. Bladder volume, ml ( n = 9 1 , 8 females, 1 male) ICIQ‐FLUTS ( n = 10 females) ICIQ‐Bowel ( n = 11, 10 females, 1 male) ICIQ‐FLUTSsex ( n = 8 females) EQ‐5D‐5L ( n = 11, 10 females, 1 male)
n
= 4, SG
n
= 5, TG
n
= 5, SG
n
= 5, TG
Baseline 146 (IQR: 139; 189) 138 (IQR: 127; 163) 21 (IQR: 17; 25) 18 (IQR: 15; 20) 39 (IQR: 34; 42) 6 (IQR: 4; 7) 0.88 (IQR 0.76; 0.96) End of Test Phase 259 (IQR: 217; 296) 174 (IQR: 171; 195) 13 (IQR: 9;16) 8 (IQR: 7; 10) 14 (IQR: 26) NA 1 (IQR: 0.8; 1) End of Intervention Phase 175 (IQR: 162; 191) 175 (IQR: 164; 205) 20 (IQR: 18; 24) 6 (IQR: 5; 9) NA NA NA End of Trial 204 (IQR: 197; 231) 184 (IQR: 165; 195) 13 (IQR: 10; 15) 7 (IQR: 6; 8) 19 (IQR: 12; 30) 2 (IQR: 1; 3) 0.93 (IQR: 0.85; 1) Difference between End of Intervention Phase and End of Test Phase −65 (IQR: −104; −38) 7 (IQR: 1; 10) 9 (IQR: 8; 11) −1 (IQR: −2; −1) NA NA NA Difference between End of Trial and End of Test Phase −13 (IQR: −45; 2) 0 (IQR: −6; 10) 0 (IQR: −1; 1) −1 (IQR: −2; 4) 1 (IQR: −3; 8) NA 0.048 (IQR 0.004; 0.098)
Note: Values represent median, Interquartile range (IQR). Dark grey cells: IPG ON. Light grey cells: IPG OFF. Abbreviations: NA, Not applicable; SG, Sham group; TG, Treatment group.
1
Nine patients had spontaneous voiding.
Changes in bladder volume, ICIQ‐FLUTS, ICIQ‐Bowel, ICIQ‐FLUTSsex and quality of life throughout the trial period.
Note: Values represent median, Interquartile range (IQR).
Dark grey cells: IPG ON.
Light grey cells: IPG OFF.
Abbreviations: NA, Not applicable; SG, Sham group; TG, Treatment group.
Nine patients had spontaneous voiding.
Overall, a reduction of more than 50% in the ICIQ‐FLUTS score from Baseline to End of Trial was observed in 6 (6/10) patients (Table 4 ).
Table 4 Changes in ICIQ‐FLUTS, ICIQ‐Bowel, ICIQ‐FLUTSsex scores, and quality of life for the ten females throughout the trial period. ID Baseline End of test phase End of intervention phase End of Trial ICIQ‐FLUTS ICIQ‐Bowel ICIQ‐FLUTS‐sex EQ‐5D‐5L ICIQ‐FLUTS ICIQ‐Bowel EQ‐5D‐5L ICIQ‐FLUTS ICIQ‐FLUTS ICIQ‐Bowel ICIQ‐FLUTS‐sex EQ‐5D‐5L
1
25 44 NA 50 16 33 80 24 10 29 NA 70
2
18 41 9 75 8 7 80 5 5 19 6 80
3
15 6 NA 55 10 7 80 9 8 5 NA 45
4
17 14 4 80 2 1 100 13 3 2 1 86
5
24 46 5 69 3 14 72 1 7 34 4 93
6
15 55 7 50 16 34 50 20 15 36 3 62
7
20 39 6 86 7 11 95 6 6 19 3 90
8
26 36 7 42 13 26 50 24 13 27 2 79
9
12 36 3 75 10 25 80 15 15 32 1 72
10
21 41 1 89 21 22 93 9 15 15 1 94
Note: Dark grey cells: IPG ON. Light grey cells: IPG OFF.
Changes in ICIQ‐FLUTS, ICIQ‐Bowel, ICIQ‐FLUTSsex scores, and quality of life for the ten females throughout the trial period.
Note: Dark grey cells: IPG ON.
Light grey cells: IPG OFF.
We observed a similar trend in the ICIQ‐FLUTSsex scores, with 8 females completing the questionnaires throughout the trial. Data was collected at Baseline and at the End of Trial. It revealed a reduction in the median ICIQ‐FLUTSsex score, decreasing from 6 (IQR: 4; 7) to 2 (IQR: 1; 3) (Table 3 ). Overall, a reduction of more than 50% in the ICIQ‐FLUTSsex scores was observed in five patients (5/8) (Table 4 ).
For all the participants, 10 females and 1 male, the ICIQ‐Bowel scores were reduced by a median from 39 (IQR: 34; 42) at Baseline to 14 (IQR: 9; 26) at the End of Test Phase. This improvement was maintained at the End of Trial with a median difference of 1 (IQR: −3; 8) (Table 3 ). Overall, 5 (5/11) patients, 4 females and 1 male, had more than 50% reduction in the ICIQ‐Bowel scores, most significantly in the domain of QoL (Table 4 ).
When assessing QoL, we observed median difference in EQ‐5Q‐5L score of 0.05 (IQR: 0.004; 0.1) from Baseline to End of Trial.
Assessment of GAS revealed that majority of patients were satisfied with the treatment. At the End of Trial, 6 patients (6/11) were completely satisfied, three patients (3/11) were mostly satisfied, and two patients (2/11) stated to be neither satisfied nor dissatisfied with treatment (Table 3 ).
Discussion
This pilot trial demonstrated that nearly half of the MS patients with refractory NLUTD, who were screened met the inclusion criteria for participation. Of these, the majority were responders at the End of Test Phase. By the end of the trial, 8/11 patients sustained the positive response.
The study tools, including patient information, questionnaires, and bladder diaries, were generally found to be feasible and easy to understand, though some initial challenges were noted with the pad test at Baseline. These challenges were significantly reduced by the End of Trial, pointing out the need of extensive patient education on how to perform PWT during the future RCT.
Participants effectively managed the SNM control throughout the trial. Apart from one case of repeated device‐related issues, treatment parameters were easily adjusted as needed. The therapy was safe and well‐tolerated, by the patients in both active treatment and sham groups.
Overall, approximately half of the participants achieved more than a 50% reduction in PROMs for urinary, bowel, and sexual symptoms during the trial, with the most significant improvements observed in the ICIQ‐FLUTS scores. The changes in both BD‐derived variables and PROMs correlated with stimulation ON or OFF during the respective phases of the trial, demonstrating improvement in both subjective and objective parameters during active stimulation. However, the sample size was too small to draw definitive conclusions, supporting the need for future RCT.
Which MS Patients Could Benefit From SNM?
MS patients exhibit a wide spectrum of urinary symptoms, leading to variable responses to SNM when used in treating NLUTD. This variability results in varying reports on the efficacy of SNM in this patient group. Minardi et al. reviewed a case series of 25 MS patients and found that SNM showed promising results for those with urinary frequency, but a low success rate in patients with urinary retention [ 18 ]. Andretta et al. conducted an observational retrospective survey in 17 MS patients treated with SNM, discovering favorable outcomes in those with either storage or voiding symptoms, but not in those with a combination of these symptoms [ 19 ]. Van Ophoven et al. reviewed systematically the efficacy of SNM for patients with different neurological disease, including 94 MS patients. They observed that the success rate of the SNM in the testing phase was 61% in neurogenic detrusor overactivity, 52% in neurogenic non‐obstructive urinary retention and 69% in the group with mixed symptoms. The evidence regarding who would benefit most from SNM remains inconclusive. In our observations, SNM generally proved effective and showed benefits across all groups of NLUTD.
Similarly, there are conflicting findings in the literature regarding type of MS and level of disability of patients that might benefit from SNM. In a prospective study, Peters et al. suggested that both patients with progressive and nonprogressive neurological conditions would benefit from SNM [ 20 ]. However, Chaabane et al. reported that SNM may fail in patients due to disease progression, recommending the therapy only for those with relapsing‐ remitting MS who have not experienced a relapse for at least 2 years [ 21 ]. Despite these varying perspectives, it is generally accepted, that SNM should be considered only for patients with stable disease over the 6‐12 months without major motor dysfunction [ 6 , 22 ].
The Effect of SNM on Bowel and Sexual Function and Overall Quality of Life (QoL)
Throughout the trial, PROMs demonstrated improvement not only in urinary symptoms but also in bowel and sexual symptoms, indicating that these enhancements may influence overall satisfaction with the treatment. These results correspond with several published studies, which demonstrated efficacy of SNM in treating fecal incontinence and sexual dysfunction in patients with MS [ 5 , 6 , 18 , 22 , 23 ].
There is no consensus on how to measure the impact of the treatment of NLUTD on overall QoL. Pericolini et al. suggested that using a bladder diary in association with PROMs is a simple and effective method to objectively evaluate the treatment's impact on patients' QoL [ 24 ]. In our study, we used EQ‐5D‐5L questionnaire. With this instrument, we observed only minimal changes over the study period. This may be attributed to plethora of other MS‐related disabilities and the nonspecific nature of this questionnaire. Therefore, we continue to search for optimal method to measure the impact of SNM treatment on QoL for the future RCT.
Blinding and Stimulation Parameters
During programming, we set the stimulation intensity at a subsensory threshold in all patients. This approach was guided by findings from previous studies indicating that subsensory and sensory stimulation achieve similar clinical outcomes [ 25 ]. Additionally, this strategy was part of the preparation for a future RCT aimed at exploring the feasibility of blinding both patients and the primary investigator to the stimulation settings.
There is little evidence about the stimulation amplitudes for neurological patients. In our trial the median stimulation value after implantation of the IPG was 0.6 V (range 0.2−1.5 V). This is in contrast to the findings in the case series by Minardi et al. who used a mean amplitude of 3.6 V (range 2.3−5.8 V) [ 18 ]. Based on these results van Ophoven et al. suggested that neurological patients need higher stimulation amplitudes compared to standard non‐neurogenic SNM patients [ 6 ]. Our data contradict with these findings, showing improvements while using subsensory stimulation at a lower amplitude.
Strengths and Limitations of This Study
In our pilot trial, we aimed to evaluate the feasibility and safety of a sham‐controlled SNM method designed for use in a randomized double‐blind sham‐controlled trial assessing the efficacy of SNM in treating refractory NLUTD of MS patients. A key strength of this trial is the inclusion of a sham control group, which not only minimizes the placebo effect but also evaluates the feasibility of implementing such a control in future studies.
To the best of our knowledge, this is the first prospective trial to assess the impact of SNM on MS patients with a well‐defined EDSS, ensuring a more homogeneous study population. Additionally, we expanded the scope by investigating changes in other pelvic organ functions, such as bowel and sexual functions, using validated PROMs.
The main limitations of this pilot trial include the small sample size, leading to unequal representation in terms of age, different NLUTD subgroups, and sex. The results primarily reflect promising outcomes in a female MS‐population, as only one male was included in the study. As a result, definitive conclusions cannot be drawn from our secondary outcomes.
Conclusions
SNM appears to be a feasible, safe and promising treatment option for MS patients with refractory NLUTD. However, more robust data are needed to confirm its efficacy. Based on the findings from this pilot trial, we plan to conduct a multicenter, double‐blinded, sham‐controlled RCT.
Author Contributions
Hanne Kobberø: conceptualization, data curation, funding, acquisition, investigation, methodology, management, resources, software, visualization, original draft preparation. Jan Krhut: conceptualization, methodology, validation, visualization, review and editing. Peter Zvara: conceptualization, methodology, validation, visualization, review and editing. Torben Brøchner Pedersen: formal analysis, software, visualization, review and editing. Mikkel Fode: conceptualization, methodology, validation, visualization, review and editing. Helle Hvilsted Nielsen: supervision, visualization, review and editing. Mads Hvid Poulsen: methodology, supervision, visualization, review and editing.
Ethics Statement
Ethics approval for the conduct of this study was obtained from the Ethics Committee Southern Denmark on the 31st of May 2021 with the project ID S‐20210030. All participants were treated according to current clinical standards regardless of the randomized study participation. The participants were volunteers and could, at any moment, withdraw their participation in the study without affecting their current or future treatment rights. The approval Ethical Committee on Health Research Ethics for Southern Denmark: No. 77525.
Consent
The Informed Consent form was handed out and would be signed by all participants willing to participate the study and stored in their electronic journals in Department of Urology, Odense University Hospital. All patients were given both oral and written information about the study.
Conflicts of Interest
Financial competing interests: Hanne Kobberø is a consultant for Medtronic. Jan Krhut serves as a consultant for Medtronic, Stimvia, Promedon, and Coloplast. Non‐financial competing interests: Mikkel Fode is a speaker and advisory board member for Astellas. During the trial, all authors will comply with their respective institution's policies on conflicts of interest.
Permission to Reproduce Material From Other Sources
Not relevant. We used our own original data.
Acknowledgments
This trial was funded by the Multiple Sclerosis Association, Denmark, The Department of Urology, Odense University Hospital, Faculty scholarship, the University of Southern Denmark.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author, Hanne Kobberø, upon reasonable request. The project is registered at OPEN, Odense Patient data Explorative Network, Odense University Hospital, Odense, Denmark with file number: OP_1411. The project is approved by the Danish Data Protection Agency 21/31796 in Region South Denmark.
References
Associated Data
Data Availability Statement
The data that support the findings of this study are available from the corresponding author, Hanne Kobberø, upon reasonable request. The project is registered at OPEN, Odense Patient data Explorative Network, Odense University Hospital, Odense, Denmark with file number: OP_1411. The project is approved by the Danish Data Protection Agency 21/31796 in Region South Denmark.
Bladder Diary
Body Mass Index
Clean Intermittent Catheterization
Expanded Disability Status Scale
European Quality of Life 5 Dimensions Questionnaire
Global Assessment Scale
International Consultation on Incontinence Questionnaires Anal Incontinence Symptoms and Quality of Life
International Consultation on Incontinence Questionnaires about Female Lower Urinary Tract Symptoms
International Consultation on Incontinence Questionnaires about Female Sexual Matters Associated with Lower urinary Tract Symptoms
International Consultation on Incontinence Questionnaires about Male Lower Urinary Tract Symptoms
International Consultation on Incontinence Questionnaires about Male Sexual Matters Associated with Lower urinary Tract Symptoms
Implantable Pulse Generator
Interquartile Range
Milliampere
Multiple Sclerosis
Neurogenic Lower Urinary Tract Dysfunction
Patient Related Outcome Measure
Post‐void Residuals
Pad Weight Test
Maximum Urine Flow Rate, mL/s
Quality of Life
Randomized Controlled Trial
Relapsing‐Remitting Multiple Sclerosis
Sham Group
Sacral Neuromodulation
Treatment Group
Volt
Introduction
Multiple sclerosis (MS) is a chronic inflammatory, neurodegenerative and progressive disorder causing demyelination and axonal loss in the central nervous system [ 1 ]. The symptomatology includes neurogenic lower urinary tract dysfunction (NLUTD) as well as bowel and sexual dysfunctions [ 2 ].
The incidence of urinary symptoms increases with disease duration and involvement of the motor system [ 1 ]. After ten years with MS, nearly all patients experience urinary symptoms, affecting the storage and/or voiding phase with increased urinary frequency and urgency as the most bothersome symptoms. Both neurogenic bowel and sexual dysfunction affect around 50% of MS patients [ 2 ].
According to European and US guidelines, the treatment options for NLUTD encompass behavioral therapy, various catheterization methods, oral drugs and bladder injections with Onabotulinum Toxin A. For more severe cases, surgical interventions such as bladder augmentation may be considered [ 3 , 4 ].
Since 2020, SNM devices have become fully MRI‐compatible, making SNM an attractive option for MS patients, who require regular MRI monitoring as part of their follow‐up. However, no dedicated randomized controlled trials (RCTs) have been conducted specifically for this patient group [ 5 , 6 ].
The aim of this pilot trial is to investigate the feasibility of conducting a RCT by assessing recruitment potential, response rate, protocol adherence, and obtaining key safety and efficacy data required for planning of a future RCT in MS patients.
Materials and Methods
The trial was conducted in accordance with the principles of the Declaration of Helsinki, the World Medical Association, and the CONSORT 2010 statement [ 7 ]. The study protocol was approved by the Ethical Committee on Health Research Ethics for Southern Denmark No. 77525. All participants provided written informed consent. The trial was registered on ClinicalTrials. gov NCT05380856 .
Participants
We enrolled adult MS patients with NLUTD, i.e. urgency frequency and/or incontinence or chronic urinary retention. These patients were refractory to conservative treatment such as lifestyle modifications, antimuscarinics and/or beta‐3 agonists.
Inclusion criteria were: Diagnosis of MS according to the revised McDonald Criteria 2017 [ 8 ], Expanded Disability Status Scale (EDSS) less than 5, no progression of neurological disease within 6 months, and ability to handle the SNM control unit. Exclusion criteria included urological, bowel or gynecological pathology caused by diseases other than MS, bladder injections with OnabotulinumToxin A within 6 months, and percutaneous tibial nerve stimulation within 2 months before inclusion.
Study Design
This was a single‐center randomized two‐arm parallel‐group, non‐blinded pilot trial. Eligible subjects underwent a complete neuro‐urological investigation including a 3‐day bladder diary (BD), questionnaires of patient related outcome measures (PROMs), uroflowmetry, post‐void residual measurement (PVR), cystoscopy and imaging of the kidneys to assess baseline characteristics ( Baseline ). The patients were categorized into three subgroups of NLUTD, according to their predominant symptoms (urgency/urgency incontinence, chronic urinary retention, combination of both).
After baseline assessments, enrolled patients underwent implantation of the tined lead electrode using the standardized electrode placement technique [ 9 ]. At the subsequent programming, a subsensory threshold of stimulation was chosen. After 4 weeks of SNM testing ( End of Test Phase), the treatment response was evaluated by 3‐day BD and PROMs. Responders were defined as patients who achieved a 50% or greater improvement in key BD‐derived variables compared to Baseline [ 10 ].
Responders were implanted with implantable pulse generator (IPG). All patients, but one, were implanted with non‐rechargeable InterStim II, while one patient had the InterStim Micro rechargeable IPG (Medtronic Inc. Minneapolis, MN, USA). Subsequently, patients were non‐blindly randomized in a 1:1 ratio to either the treatment or sham group, using a computer‐generated list. Patients assigned to the treatment group were stimulated at 0.1–0.2 V below the sensory threshold for the next 4 weeks, while patients assigned to the sham group were kept without stimulation for the same duration. At the End of Intervention Phase , all patients were assessed using a 3‐day BD and PROMs.
Subsequently, the patients in the sham group had their stimulation activated and all the subjects were stimulated for additional 4 weeks, at which point the trial was concluded ( End of Trial ). The final evaluation was performed with 3‐day bladder diaries, PROMs, global assessment scale (GAS), uroflowmetry with maximum urine flow rate (Qmax), and post‐void residual (PVR).
The trial flow is depicted in Figure 1 .
Overview of the Trial Flow. Schematic summary of the study design. The columns describe the phases of the trial in chronological order (from left to right). ICIQ‐M/FLUTS: International Consultation on Incontinence Questionnaires about Male/Female Lower Urinary Tract Symptoms. ICIQ‐M/FLUTSsex: International Consultation on Incontinence Questionnaires about Male/Female Sexual Matters Associated with Lower urinary Tract Symptoms. EQ‐5D‐5L, European Quality of Life 5 Dimensions Questionnaire; GAS, Global Assessment Scale.
Study Assessments
Three‐day BD was recorded before each of the study timepoints. Numbers of voids, voided volume, numbers of urge urinary incontinence episodes, and pad weight test (PWT) were recorded in patients with spontaneous voiding and leading symptom of urgency/urgency incontinence, while numbers of clean intermittent catheterization (CIC) episodes and catheterized volume were recorded in patients with chronic urinary retention. All above mentioned variables were recorded in patients with both symptoms [ 10 ].
As PROMs, the validated Danish language International Consultation on Incontinence Questionnaires about Male Lower Urinary Tract Symptoms (ICIQ‐MLUTS) [ 11 ], Male Sexual Matters Associated with Lower urinary Tract Symptoms (ICIQ‐MLUTSsex) [ 12 ], Female Lower Urinary Tract Symptoms (ICIQ‐FLUTS) [ 13 ], Female Sexual Matters Associated with Lower urinary Tract Symptoms (ICIQ‐FLUTSsex) [ 14 ], and Anal Incontinence Symptoms and Quality of Life (ICIQ‐Bowel) [ 15 ] were used. In all questionnaires, higher scores signify higher symptom severity and higher impact on the quality of life.
To evaluate the impact of treatment on general health‐related quality of life (QoL), the European Quality of Life 5 Dimensions questionnaire (EQ‐5D‐5L) [ 16 ] was employed. A higher EQ‐5D‐5L index, signifies better QoL.
Additionally, GAS was used to assess patient satisfaction with the treatment. GAS is a 5‐point Likert scale ranging from complete dissatisfaction to completely satisfaction with the treatment.
Serious adverse events were monitored continuously according to MDCG 2020‐10/2 Clinical Investigation Summary Safety Report Form v1.0 [ 17 ].
We also monitored the stimulation parameters.
Endpoints
Primary endpoints were recruitment potential (numbers of patients eligible/numbers of patients screened in the trial), adherence to the protocol, and proportion of responders defined as more than a 50% improvement of key bladder variables at the End of Test Phase compared to Baseline.
Secondary endpoint was safety. In addition, we assessed changes in key BD variables, PROMs, patient satisfaction and QoL.
Statistical Analysis
Descriptive statistics to measure the central tendency was conducted using R version 4.3.3 (2024‐02‐29) software. The values are reported as median with range (min. – max.) or median with interquartile range (IQR). Given the low number of participants, further statistical analyses of the efficacy outcomes was not feasible.
Results
Patients, Study Feasibility, Recruitment Potential and Protocol Adherence
Between September 2021 to June 2023, 32 individuals were screened for participation. Of these, 17 (17/32) subjects were eligible for the study. Four subjects declined to participate. Thirteen patients met the inclusion criteria, provided consent, and were enrolled in the trial (Figure 2 ).
Consolidated Standards of Reporting Trials (CONSORT) diagram of the trial. IPG, Implantable Pulse Generator; NLUTD, Neurogenic Lower Urinary Tract Dysfunction.
Among the participants, 10 were females. The median age was 53 (min. 44–max. 62) years. All but one patient had relapsing/remitting MS with a median EDSS of 4.0 (min. 2.5–max. 4.5) (Table 1 ).
Table 1 Demographic and clinical characteristics of the study population. ID Sex Age (Years) MS type Duration of MS (Years) EDSS BMI NLUTD Allocation 1 Female 61 SPMS 15 2.5 30.9 Urgency/Urgency Incontinence TG 2 Female 62 RRMS 38 4.0 21.9 Urgency/Urgency Incontinence TG 3 Female 53 RRMS 15 4.0 30.9 Urgency/Urgency Incontinence TG 4 Female 49 RRMS 14 4.0 23.7 Urgency/Urgency Incontinence TG 5 Female 44 RRMS 16 4.5 25.7 Urgency/Urgency Incontinence SG 6 Female 59 RRMS 14 2.5 38.1 Chronic Urinary Retention SG 7 Female 59 RRMS 31 4.5 26.2 Chronic Urinary Retention TG 8 Female 45 RRMS 13 4.0 23.8 Combination SG 9 Female 48 RRMS 23 4.5 24.7 Combination SG 10 Female 58 RRMS 10 4.5 25.3 Combination TG 11 Male 51 RRMS 13 3.5 32.4 Combination SG Abbreviations: BMI, Body Mass Index; EDSS, Expanded Disability Status Scale; MS, Multiple Sclerosis; NLUTD, Neurogenic lower urinary tract dysfunction; RRMS, Relapsing‐Remitting Multiple Sclerosis¨; SG, Sham Group; SPMS, Secondary Progressive Multiple Sclerosis; TG, Treatment Group.
Demographic and clinical characteristics of the study population.
Abbreviations: BMI, Body Mass Index; EDSS, Expanded Disability Status Scale; MS, Multiple Sclerosis; NLUTD, Neurogenic lower urinary tract dysfunction; RRMS, Relapsing‐Remitting Multiple Sclerosis¨; SG, Sham Group; SPMS, Secondary Progressive Multiple Sclerosis; TG, Treatment Group.
At the End of Test Phase, 11 (11/13) patients (Five with urgency/urgency incontinence, 2 with chronic urinary retention, and 4 with a combination) were responders and subsequently were randomized into either treatment group (6 patients) or sham group (5 patients). Two patients were excluded; one male due to technical problems with the external stimulator and one female who did not respond to the treatment (Table 1 ).
All randomized patients attended the study visits, with no dropouts. All participants were able to record 3‐day BD and complete all questionnaires. Several patients were unable to complete the PWT during the trial (Table 2 ).
Table 2 Bladder diary‐derived variables in individuals throughout the trial period*. ID Baseline End of Test Phase End of intervention phase End of trial No. voids Blad Vol. ml No. CIC Vol. CICml No. leaks/day PWT No. voids Blad Vol. ml No. CIC Vol. CIC ml No. leaks/day PWT No. voids Blad Vol. ml No. CIC Vol. CIC ml No. leaks/day PWT No. voids Blad Vol. ml No. CIC Vol. CIC ml No. leaks/day PWT
URGENCY
1
8 152 NAN NA 3.7 UK 6 224 NA NA 0 0 9 183 NA NA 1 UK 9 200 NA NA UK UK
2
9 139 NA NA 1.7 66.5 10 174 NA NA 0 0 8 175 NA NA 0 0 10 185 NA NA 0 0
3
12 163 NA NA UK UK 8 195 NA NA 0 0 8 205 NA NA 0 0 9 195 NA NA 0 0
4
14 300 NA NA 1 UK 9 304 NA NA 0 0 14 215 NA NA 0 0 9 248 NA NA 0 0
5
9 248 NA NA 5.3 9 9 255 NA NA 0 0 6 343 NA NA 0 0 9 302 NA NA 0 0
RETENTION
6
NA NA 11 82 NA NA NA NA 9 139 NA NA NA NA 11 113 NA NA NA NA 8 110 NA NA
7
NA NA 12 220 NA NA NA NA 6 280 NA NA 1 *
67 *
4 314 NA NA 1 *
67 *
6 282 NA NA
COMBINATION
8
10 132 10 148 1.6 4 10 195 5 108 1.6 9.5 12 167 8 119 1.6 18 10 208 5 101 2.3 UK
9
22 102 2 208 0 0 10 144 2 333 0 0 15 151 2 267 0 0 14 127 2 236 0 0
10
9 141 7 101 3.3 158 7 294 6 54 1.3 36 10 148 7 114 1.3 19 9 187 2 80 2.5 36.5
11
15 127 2 174 1.5 UK 9 171 0 0 0 0 10 164 0 0 0 0 13 165 0 0 0 0
Note: Numbers represent mean values. Dark grey cells: IPG ON. Light grey cells: IPG OFF. Abbreviations: Blad Vol., Bladder Volume; CIC, Clean Intermittent Catheterization; PWT, Pad Weight Test; UK, Unkown. * Spontaneous voiding in retention group.
Bladder diary‐derived variables in individuals throughout the trial period*.
Note: Numbers represent mean values.
Dark grey cells: IPG ON.
Light grey cells: IPG OFF.
Abbreviations: Blad Vol., Bladder Volume; CIC, Clean Intermittent Catheterization; PWT, Pad Weight Test; UK, Unkown.
Spontaneous voiding in retention group.
Safety
The treatment was well tolerated. Aside from postoperative pain, which was managed with paracetamol and nonsteroidal anti‐inflammatory drugs, no treatment‐related or serious adverse events were reported during the trial.
At the End of the Test Phase, the device was easily removed without complication in both non‐responders, and their bladder condition returned to the pretreatment level.
C hanges in BD‐Derived Variables
At the End of Intervention Phase, 5 patients (5/6) in the treatment group and 1 patient (1/5) in the sham group maintained a 50% improvement in BD‐derived variables.
At the End of Trial, 8 of the 11 responders maintained a 50% improvement in BD‐derived variables. The most notable improvements were observed in numbers of urge urinary incontinence episodes among patients with symptoms of urgency/urgency incontinence and in the numbers of CIC in the combination symptoms subgroup (Table 2 ).
Changes in Uroflowmetry and PVR
Uroflowmetry including Qmax and PVR were assessed at Baseline and at the End of Trial. Nine (9/11) patients voided spontaneously throughout the trial. The median voided volume increased from 203 mL (IQR: 188; 270) to 238 mL (IQR: 180; 431). Similarly, both Qmax and PVR increased with a median from 19 mL/sec (IQR: 11; 22) to 25 mL/sec (IQR: 20; 34) and the median PVR increased from 55 mL (IQR: 33; 110) to 131 mL (IQR: 69; 164).
Changes in PROMs
Significant reduction in ICIQ‐FLUTS scores was observed from a median 19.0 (IQR: 16; 23) at Baseline to the 9.5 (IQR: 7; 12) at the End of the Test Phase.
At the End of Intervention Phase, the ICIQ‐FLUTS score remained stable in the treatment group with a median change of ‐1 (IQR: −2; −1), whereas the sham group experienced a substantial increase of 9 (IQR: 8; 11) compared to End of Test Phase.
By the End of Trial, ICIQ‐FLUTS scores in the patients assigned to the sham group showed improvement to the level of End of the Test Phase. Patients in the treatment group maintained similar ICIQ‐FLUTS scores (Table 3 ).
Table 3 Changes in bladder volume, ICIQ‐FLUTS, ICIQ‐Bowel, ICIQ‐FLUTSsex and quality of life throughout the trial period. Bladder volume, ml ( n = 9 1 , 8 females, 1 male) ICIQ‐FLUTS ( n = 10 females) ICIQ‐Bowel ( n = 11, 10 females, 1 male) ICIQ‐FLUTSsex ( n = 8 females) EQ‐5D‐5L ( n = 11, 10 females, 1 male)
n
= 4, SG
n
= 5, TG
n
= 5, SG
n
= 5, TG
Baseline 146 (IQR: 139; 189) 138 (IQR: 127; 163) 21 (IQR: 17; 25) 18 (IQR: 15; 20) 39 (IQR: 34; 42) 6 (IQR: 4; 7) 0.88 (IQR 0.76; 0.96) End of Test Phase 259 (IQR: 217; 296) 174 (IQR: 171; 195) 13 (IQR: 9;16) 8 (IQR: 7; 10) 14 (IQR: 26) NA 1 (IQR: 0.8; 1) End of Intervention Phase 175 (IQR: 162; 191) 175 (IQR: 164; 205) 20 (IQR: 18; 24) 6 (IQR: 5; 9) NA NA NA End of Trial 204 (IQR: 197; 231) 184 (IQR: 165; 195) 13 (IQR: 10; 15) 7 (IQR: 6; 8) 19 (IQR: 12; 30) 2 (IQR: 1; 3) 0.93 (IQR: 0.85; 1) Difference between End of Intervention Phase and End of Test Phase −65 (IQR: −104; −38) 7 (IQR: 1; 10) 9 (IQR: 8; 11) −1 (IQR: −2; −1) NA NA NA Difference between End of Trial and End of Test Phase −13 (IQR: −45; 2) 0 (IQR: −6; 10) 0 (IQR: −1; 1) −1 (IQR: −2; 4) 1 (IQR: −3; 8) NA 0.048 (IQR 0.004; 0.098)
Note: Values represent median, Interquartile range (IQR). Dark grey cells: IPG ON. Light grey cells: IPG OFF. Abbreviations: NA, Not applicable; SG, Sham group; TG, Treatment group.
1
Nine patients had spontaneous voiding.
Changes in bladder volume, ICIQ‐FLUTS, ICIQ‐Bowel, ICIQ‐FLUTSsex and quality of life throughout the trial period.
Note: Values represent median, Interquartile range (IQR).
Dark grey cells: IPG ON.
Light grey cells: IPG OFF.
Abbreviations: NA, Not applicable; SG, Sham group; TG, Treatment group.
Nine patients had spontaneous voiding.
Overall, a reduction of more than 50% in the ICIQ‐FLUTS score from Baseline to End of Trial was observed in 6 (6/10) patients (Table 4 ).
Table 4 Changes in ICIQ‐FLUTS, ICIQ‐Bowel, ICIQ‐FLUTSsex scores, and quality of life for the ten females throughout the trial period. ID Baseline End of test phase End of intervention phase End of Trial ICIQ‐FLUTS ICIQ‐Bowel ICIQ‐FLUTS‐sex EQ‐5D‐5L ICIQ‐FLUTS ICIQ‐Bowel EQ‐5D‐5L ICIQ‐FLUTS ICIQ‐FLUTS ICIQ‐Bowel ICIQ‐FLUTS‐sex EQ‐5D‐5L
1
25 44 NA 50 16 33 80 24 10 29 NA 70
2
18 41 9 75 8 7 80 5 5 19 6 80
3
15 6 NA 55 10 7 80 9 8 5 NA 45
4
17 14 4 80 2 1 100 13 3 2 1 86
5
24 46 5 69 3 14 72 1 7 34 4 93
6
15 55 7 50 16 34 50 20 15 36 3 62
7
20 39 6 86 7 11 95 6 6 19 3 90
8
26 36 7 42 13 26 50 24 13 27 2 79
9
12 36 3 75 10 25 80 15 15 32 1 72
10
21 41 1 89 21 22 93 9 15 15 1 94
Note: Dark grey cells: IPG ON. Light grey cells: IPG OFF.
Changes in ICIQ‐FLUTS, ICIQ‐Bowel, ICIQ‐FLUTSsex scores, and quality of life for the ten females throughout the trial period.
Note: Dark grey cells: IPG ON.
Light grey cells: IPG OFF.
We observed a similar trend in the ICIQ‐FLUTSsex scores, with 8 females completing the questionnaires throughout the trial. Data was collected at Baseline and at the End of Trial. It revealed a reduction in the median ICIQ‐FLUTSsex score, decreasing from 6 (IQR: 4; 7) to 2 (IQR: 1; 3) (Table 3 ). Overall, a reduction of more than 50% in the ICIQ‐FLUTSsex scores was observed in five patients (5/8) (Table 4 ).
For all the participants, 10 females and 1 male, the ICIQ‐Bowel scores were reduced by a median from 39 (IQR: 34; 42) at Baseline to 14 (IQR: 9; 26) at the End of Test Phase. This improvement was maintained at the End of Trial with a median difference of 1 (IQR: −3; 8) (Table 3 ). Overall, 5 (5/11) patients, 4 females and 1 male, had more than 50% reduction in the ICIQ‐Bowel scores, most significantly in the domain of QoL (Table 4 ).
When assessing QoL, we observed median difference in EQ‐5Q‐5L score of 0.05 (IQR: 0.004; 0.1) from Baseline to End of Trial.
Assessment of GAS revealed that majority of patients were satisfied with the treatment. At the End of Trial, 6 patients (6/11) were completely satisfied, three patients (3/11) were mostly satisfied, and two patients (2/11) stated to be neither satisfied nor dissatisfied with treatment (Table 3 ).
Discussion
This pilot trial demonstrated that nearly half of the MS patients with refractory NLUTD, who were screened met the inclusion criteria for participation. Of these, the majority were responders at the End of Test Phase. By the end of the trial, 8/11 patients sustained the positive response.
The study tools, including patient information, questionnaires, and bladder diaries, were generally found to be feasible and easy to understand, though some initial challenges were noted with the pad test at Baseline. These challenges were significantly reduced by the End of Trial, pointing out the need of extensive patient education on how to perform PWT during the future RCT.
Participants effectively managed the SNM control throughout the trial. Apart from one case of repeated device‐related issues, treatment parameters were easily adjusted as needed. The therapy was safe and well‐tolerated, by the patients in both active treatment and sham groups.
Overall, approximately half of the participants achieved more than a 50% reduction in PROMs for urinary, bowel, and sexual symptoms during the trial, with the most significant improvements observed in the ICIQ‐FLUTS scores. The changes in both BD‐derived variables and PROMs correlated with stimulation ON or OFF during the respective phases of the trial, demonstrating improvement in both subjective and objective parameters during active stimulation. However, the sample size was too small to draw definitive conclusions, supporting the need for future RCT.
Which MS Patients Could Benefit From SNM?
MS patients exhibit a wide spectrum of urinary symptoms, leading to variable responses to SNM when used in treating NLUTD. This variability results in varying reports on the efficacy of SNM in this patient group. Minardi et al. reviewed a case series of 25 MS patients and found that SNM showed promising results for those with urinary frequency, but a low success rate in patients with urinary retention [ 18 ]. Andretta et al. conducted an observational retrospective survey in 17 MS patients treated with SNM, discovering favorable outcomes in those with either storage or voiding symptoms, but not in those with a combination of these symptoms [ 19 ]. Van Ophoven et al. reviewed systematically the efficacy of SNM for patients with different neurological disease, including 94 MS patients. They observed that the success rate of the SNM in the testing phase was 61% in neurogenic detrusor overactivity, 52% in neurogenic non‐obstructive urinary retention and 69% in the group with mixed symptoms. The evidence regarding who would benefit most from SNM remains inconclusive. In our observations, SNM generally proved effective and showed benefits across all groups of NLUTD.
Similarly, there are conflicting findings in the literature regarding type of MS and level of disability of patients that might benefit from SNM. In a prospective study, Peters et al. suggested that both patients with progressive and nonprogressive neurological conditions would benefit from SNM [ 20 ]. However, Chaabane et al. reported that SNM may fail in patients due to disease progression, recommending the therapy only for those with relapsing‐ remitting MS who have not experienced a relapse for at least 2 years [ 21 ]. Despite these varying perspectives, it is generally accepted, that SNM should be considered only for patients with stable disease over the 6‐12 months without major motor dysfunction [ 6 , 22 ].
The Effect of SNM on Bowel and Sexual Function and Overall Quality of Life (QoL)
Throughout the trial, PROMs demonstrated improvement not only in urinary symptoms but also in bowel and sexual symptoms, indicating that these enhancements may influence overall satisfaction with the treatment. These results correspond with several published studies, which demonstrated efficacy of SNM in treating fecal incontinence and sexual dysfunction in patients with MS [ 5 , 6 , 18 , 22 , 23 ].
There is no consensus on how to measure the impact of the treatment of NLUTD on overall QoL. Pericolini et al. suggested that using a bladder diary in association with PROMs is a simple and effective method to objectively evaluate the treatment's impact on patients' QoL [ 24 ]. In our study, we used EQ‐5D‐5L questionnaire. With this instrument, we observed only minimal changes over the study period. This may be attributed to plethora of other MS‐related disabilities and the nonspecific nature of this questionnaire. Therefore, we continue to search for optimal method to measure the impact of SNM treatment on QoL for the future RCT.
Blinding and Stimulation Parameters
During programming, we set the stimulation intensity at a subsensory threshold in all patients. This approach was guided by findings from previous studies indicating that subsensory and sensory stimulation achieve similar clinical outcomes [ 25 ]. Additionally, this strategy was part of the preparation for a future RCT aimed at exploring the feasibility of blinding both patients and the primary investigator to the stimulation settings.
There is little evidence about the stimulation amplitudes for neurological patients. In our trial the median stimulation value after implantation of the IPG was 0.6 V (range 0.2−1.5 V). This is in contrast to the findings in the case series by Minardi et al. who used a mean amplitude of 3.6 V (range 2.3−5.8 V) [ 18 ]. Based on these results van Ophoven et al. suggested that neurological patients need higher stimulation amplitudes compared to standard non‐neurogenic SNM patients [ 6 ]. Our data contradict with these findings, showing improvements while using subsensory stimulation at a lower amplitude.
Strengths and Limitations of This Study
In our pilot trial, we aimed to evaluate the feasibility and safety of a sham‐controlled SNM method designed for use in a randomized double‐blind sham‐controlled trial assessing the efficacy of SNM in treating refractory NLUTD of MS patients. A key strength of this trial is the inclusion of a sham control group, which not only minimizes the placebo effect but also evaluates the feasibility of implementing such a control in future studies.
To the best of our knowledge, this is the first prospective trial to assess the impact of SNM on MS patients with a well‐defined EDSS, ensuring a more homogeneous study population. Additionally, we expanded the scope by investigating changes in other pelvic organ functions, such as bowel and sexual functions, using validated PROMs.
The main limitations of this pilot trial include the small sample size, leading to unequal representation in terms of age, different NLUTD subgroups, and sex. The results primarily reflect promising outcomes in a female MS‐population, as only one male was included in the study. As a result, definitive conclusions cannot be drawn from our secondary outcomes.
Conclusions
SNM appears to be a feasible, safe and promising treatment option for MS patients with refractory NLUTD. However, more robust data are needed to confirm its efficacy. Based on the findings from this pilot trial, we plan to conduct a multicenter, double‐blinded, sham‐controlled RCT.
Author Contributions
Hanne Kobberø: conceptualization, data curation, funding, acquisition, investigation, methodology, management, resources, software, visualization, original draft preparation. Jan Krhut: conceptualization, methodology, validation, visualization, review and editing. Peter Zvara: conceptualization, methodology, validation, visualization, review and editing. Torben Brøchner Pedersen: formal analysis, software, visualization, review and editing. Mikkel Fode: conceptualization, methodology, validation, visualization, review and editing. Helle Hvilsted Nielsen: supervision, visualization, review and editing. Mads Hvid Poulsen: methodology, supervision, visualization, review and editing.
Ethics Statement
Ethics approval for the conduct of this study was obtained from the Ethics Committee Southern Denmark on the 31st of May 2021 with the project ID S‐20210030. All participants were treated according to current clinical standards regardless of the randomized study participation. The participants were volunteers and could, at any moment, withdraw their participation in the study without affecting their current or future treatment rights. The approval Ethical Committee on Health Research Ethics for Southern Denmark: No. 77525.
Consent
The Informed Consent form was handed out and would be signed by all participants willing to participate the study and stored in their electronic journals in Department of Urology, Odense University Hospital. All patients were given both oral and written information about the study.
Conflicts of Interest
Financial competing interests: Hanne Kobberø is a consultant for Medtronic. Jan Krhut serves as a consultant for Medtronic, Stimvia, Promedon, and Coloplast. Non‐financial competing interests: Mikkel Fode is a speaker and advisory board member for Astellas. During the trial, all authors will comply with their respective institution's policies on conflicts of interest.
Permission to Reproduce Material From Other Sources
Not relevant. We used our own original data.
Acknowledgments
This trial was funded by the Multiple Sclerosis Association, Denmark, The Department of Urology, Odense University Hospital, Faculty scholarship, the University of Southern Denmark.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author, Hanne Kobberø, upon reasonable request. The project is registered at OPEN, Odense Patient data Explorative Network, Odense University Hospital, Odense, Denmark with file number: OP_1411. The project is approved by the Danish Data Protection Agency 21/31796 in Region South Denmark.
References
Associated Data
Data Availability Statement
The data that support the findings of this study are available from the corresponding author, Hanne Kobberø, upon reasonable request. The project is registered at OPEN, Odense Patient data Explorative Network, Odense University Hospital, Odense, Denmark with file number: OP_1411. The project is approved by the Danish Data Protection Agency 21/31796 in Region South Denmark.