Abstract
Background:
Treatments for fecal incontinence (FI) remain unsatisfactory because they do not remedy the underlying multifactorial dysfunction(s) including anorectal neuropathy. Aims: To investigate the optimal dose frequency, clinical effects and safety of a novel treatment, translumbosacral neuromodulation therapy (TNT), aimed at improving neuropathy.
Methods:
FI patients were randomized to receive 6 sessions of weekly TNT treatments consisting of 600 repetitive magnetic stimulations over each of 2 lumbar and 2 sacral sites with either 1 Hz, 5 Hz or 15 Hz frequency. Stool diaries, FI severity indices, anorectal neurophysiology and sensori-motor function and quality of life (QOL) were compared. Primary outcome measure was change in FI episodes/week. Responders were patients with ≥50% decrease in weekly FI episodes.
Results:
Thirty-three FI patients participated. FI episodes decreased significantly (Δ ±95% CI, 4.2±2.8 (1 Hz); 2±1.7 (5 Hz); 3.4±2.5 (15 Hz); p<0.02) in all three groups when compared to baseline. The 1 Hz group showed a significantly higher (p=0.04) responder rate (91±9.1%) when compared to 5 Hz (36±18.2%) or 15 Hz (55±18.2%); no difference between 5 and 15 Hz (p=0.667). Anal neuropathy, squeeze pressure and rectal capacity improved significantly only in 1 Hz (p<0.05) compared to baseline but not in other groups. QOL domains improved significantly (p<0.05) with 1 and 5 Hz. No device related serious adverse events.
Conclusions:
TNT significantly improves FI symptoms in the short-term, and the 1 Hz frequency was overall better than 5 Hz and 15 Hz. Both anorectal neuropathy and physiology significantly improved, demonstrating mechanistic improvement. TNT is a promising, novel, safe, efficacious, and non-invasive treatment for FI.
Keywords: Translumbosacral, Neuromodulation Therapy, Fecal Incontinence, Neurophysiology, Anorectal Function
INTRODUCTION
Fecal incontinence (FI) affects 8-15% of the ambulatory population in USA,1, 2 predominantly women and the elderly, and 45% of nursing home residents.3, 4 It adversely affects quality of life and psychosocial function and poses a major health care burden.5 A significant problem has been a lack of effective therapies for FI, largely because of the absence of mechanistically based non-invasive therapies, and a dearth of understanding on how treatments affect the core pathophysiological mechanisms of FI.
Although several risk factors for FI have been identified that include obstetric and surgical trauma, diabetes, diarrhea and neurologic conditions, the pathophysiology of FI is also driven by structural (anal sphincters, puborectalis), sensory (rectal sensation), accommodation (rectal capacity), stool characteristics (diarrhea) and anorectal neuropathy.6–8 In fact more than one of these factors was responsible for FI in over 80% of patients.6, 7 Also, women with sphincter defects were more likely to develop incontinence if they had neuropathy,9 and in asymptomatic nulliparous women, increased age was associated with neurogenic injury, which partly explains their weak squeeze pressures.
Until recently, however, the assessment of pelvic neuropathy has been challenging7. The advent of translumbosacral anorectal magnetic stimulation (TAMS) test that uses minimally invasive magnetic stimulation of the lumbar and sacral nerve plexi to record the anal and rectal motor evoked potentials (MEPs) has enabled improved detection of neuropathy. In studies of patients with moderately severe FI, and spinal cord injury both anal and rectal MEP latencies were significantly prolonged when compared to healthy controls.8,9 Recently, in a study of brain-gut axis, these findings were further reaffirmed,10 and peripheral lumbo-anorectal and sacro-anorectal neuropathy was found to be the primary locus for neuronal derangement, and the neuropathy was often asymmetrical and patchy.10 These findings indicate that a progressive anorectal neuropathy could play a significant role in the pathogenesis of FI.6,11
We hypothesized that repetitive translumbar magnetic stimulation (rTLMS) and transsacral magnetic stimulation (rTSMS) at one or more frequency, will significantly improve FI symptoms through neuroplasticity, i.e. the ability of the nervous system to adapt and change in response to repetitive stimulation, and by enhancing both the peripheral and central neural excitability. This approach stems from our preliminary studies which suggested that translumbosacral neuromodulation therapy (TNT) improves neuropathy and anorectal pain in patients with levator ani syndrome,12 and induces central neuroplastic changes that are frequency-dependent in FI,13, 14 and those of others showing that sacral nerve stimulation enhances somato sensory cortical changes and expression of neural markers in rats .15 If so TNT could provide a multidimensional therapeutic benefit - enhance anal muscle strength, improve neuropathy, improve stool awareness and improve rectal capacity.
Our aims were to test the feasibility, clinical effects, safety and optimal frequency (dose) of TNT in patients with FI who were randomized to receive one of three frequencies (1 Hz, 5 Hz or 15 Hz) of repetitive translumbar and transsacral magnetic stimulations. We assessed the impact of treatment with each frequency on FI episodes, bowel symptoms, FI severity, and quality of life, both within each group and between groups. We also determined the mechanistic effects of TNT on the underlying pathophysiology of FI by examining the changes in anorectal and neurophysiological function.
METHODS
Patients with FI were recruited from 2 academic centers, Augusta, USA and Manchester, UK. Study was conducted between April 2015 and March 2018. All patients had a structured interview and received a physical examination, a colonoscopy to exclude structural pathology and biochemical evaluation as well as, anorectal manometry, anal ultrasound and TAMS test, see below. Once eligible for screening, participants signed an informed consent approved by the human ethics board (No. 619411). They first maintained a 2-week prospective stool diary in which they recorded their daily stool habit, number of incontinence episodes, whether stools were formed or loose on a Bristol Stool Form Scale (BSFS), whether they used pads, severity of leakage amount (1= mild, 2 = moderate, 3 = excessive), whether they experienced stool urgency, and medications for stooling.16,17 The inclusion criteria were a history of recurrent episodes of FI for 6 months that was nonresponsive to diet, fiber, antidiarrheals and Kegels exercise; and absence of colonic mucosal disease (colonoscopy + biopsy), and on a 2-week stool diary, patients reported at least one episode of solid or liquid FI/week. Patients were excluded if they had severe diarrhea (≥6 liquid stools/day, Bristol scale ≥6), were on opioids, tricyclics (except on stable doses > 3 months), severe depression, severe comorbid illnesses such as cardiac disease, COPD or chronic renal failure, previous gastrointestinal surgery, neurologic diseases (e.g. head injury, epilepsy, multiple sclerosis, strokes, spinal cord injury), impaired cognizance (mini mental score of < 15/25) and/or legally blind, metal implants, pacemakers, radical hysterectomy, ulcerative and Crohn’s colitis, rectal prolapse or inflamed hemorrhoids. Patients were allowed to continue their baseline antidiarrheals, bile sequestrants or fiber supplements throughout the study.
Study Protocol (See Flow Chart, Fig.1):
Figure 1.
Consort flow diagram of study participants.
Enrolled patients filled out a detailed questionnaire about their bowel symptoms and FI, as well as the Fecal Incontinence Severity Index (FISI) ,18 Fecal Incontinence Symptom Severity (FISS),19 Fecal incontinence quality of Life (FI-QOL),20 and a Subject Global Assessment Scale (SGA), both at baseline and end of study.
Next, patients underwent a high resolution anorectal manometry (HRARM) and TAMS tests to evaluate anorectal physiology, both at baseline and after treatment. A circumferential, 12-sensor, solid-state probe (ManoScan AR Catheter, Medtronics, MN) with a 4 cm long balloon was placed into the anorectum to perform HRARM. Details of the manometric methods have been described previously. 16, 20 Patients also underwent an anal ultrasound at baseline using standard probe (BK Medical 2052, BK Medical Holding Company, Inc. UK) and the sphincter thickness, integrity, defects and scarring were assessed.
TAMS test was performing by placing a probe into the rectum containing 2 pairs of bipolar steel ring electrodes (Gaeltec Devices Ltd., Dunvegan, Scotland). When the probe was correctly positioned, the proximal electrodes were located at 8 cm and the distal electrodes were located at 1.5 cm from the anal verge. This probe was used for recording both anal motor evoked potential (MEP) and rectal MEP.8 The magnetic stimuli were delivered using the Magstim Rapid2 stimulator (The Magstim Company Limited, Whiteland, Wales, U.K.) on each side at the L3 and the S3 levels, both about 4 cm lateral to the midline.8 At least 5 MEP recordings with an anal or rectal MEP response of at least 10 microvolts was considered adequate.
TNT therapy:
Patients were randomized to one of 3 frequencies (1 Hz, 5Hz or 15 Hz) of TNT therapy. Six sessions of treatment were given at weekly intervals. The TAMS test was used to determine the motor threshold intensity, defined as the minimum level of magnetic stimulation intensity required to achieve an anal and rectal MEP response of 10 microvolts together with fine twitching of the posterior tibialis muscle. The intensity for repetitive translumbar (rTLMS) and repetitive transsacral (rTSMS) magnetic stimulation was set at either 50% above this threshold or lower, if patient was unable to tolerate this intensity as recommended by safety guidelines.22 Next a 70 mm air film self-cooling coil (Magstim) was positioned randomly over one of the 4 sites (right or left lumbar/ right or left sacral), held in place by a coil fixator (AFC support stand, The Magstim Company Ltd, Whitland, Wales, UK) and 300 stimulations of magnetic energy were delivered (Magstim Rapid). After a 3 min rest, the cycle was repeated (Total=600 stimulations/site). The coil was moved to the next site and after a rest period of 5-10 min, the stimulations were repeated using the threshold intensity for that site. All 4 sites were stimulated (Total per session=2400 stimulations). Daily stool diaries were kept. Patients returned at weekly intervals for repeat treatment sessions. Following their last treatment session, anorectal manometry, TAMS test, FI severity measures and QOL were re-assessed.
Measurements and Outcomes:
The results obtained for the FI symptoms, physiologic and QOL measures, before and after treatment, and the differences between the 3 treatment frequencies were compared using an intention to treat analysis. The clinical, manometric and TAMS data were analyzed by an independent investigator not involved with performing TNT therapy.
The primary outcome measure was defined as the change in weekly episodes of FI. Based on this measurement we assessed the responder rate as a co-primary outcome measure. A responder was defined as an individual who showed at least 50% reduction in FI episodes after treatment. The secondary outcome measures that were assessed from the stool diaries included; stool frequency, stool consistency (Bristol Stool Form Scale, 1-7), and the use of pads. The FI severity analysis comprised of several measures including the subject global assessment (SGA) scale that assessed the overall bowel satisfaction on a VAS scale (0(absent) to10(severe)), the FISI which assessed improvement on a scale of 0(no leakage) to 61(most frequent) and the FISS scale that assessed FI on a scale of 4(mild) to-13(severe).19,23 The FI- QOL assessed the changes in 4 QOL domains that included effects on lifestyle, coping, embarrassment and depression.20
The anorectal function was assessed by the changes in anal resting, squeeze and sustained sphincter pressures,23 the rectal sensory thresholds for first sensation, urge to defecate and maximum tolerable volume, and the rectal compliance (dv/dp).21,24 The MEP latency was defined as the interval between the onset of stimulus and the onset of the individual rectal or anal MEP waveform and was expressed in milliseconds.8, 10 An abnormal MEP latency (neuropathy) was defined as a value that was higher than the 95% confidence interval of healthy controls10. A data safety monitoring board was established to oversee adverse events and adjudicate them. Data were collected on paper case report forms after performing the various assessments including prospective stool diary information, and then entered into a secure excel database, stored and backed up. Next, the data was transferred to the biostatistician for statistical analysis. This study did not include a plan for data sharing.
Power and Sample Size Calculations:
We used the relative difference in the number of FI episodes as the measure to determine the sample size for this study. We assumed that the number of FI episodes within each of the three treatment arms has a coefficient of variation (ratio of standard deviation to mean) of 0.25 (1:4). For each of the three treatment arms, to observe a 20% reduction in the number of FI episodes within the treatment arm with 80% power, at 5% significance level, a sample of 12 subjects will be needed, i.e. a total of 36 subjects.
Randomization procedures:
Subjects were randomly assigned to one of three treatment arms based on the frequency of magnetic stimulations; 1 Hz, 5 Hz or 15 Hz. The randomization schedule was generated by the biostatistician using a permuted blocks of 3 method to ensure balance among the 3 treatment arms, and at each center, while making it highly improbable to predict the next treatment assignment. Also, to assign the combination of testing conditions for each subject, we used a 2x2 factorial design – two sides of lumbar (left/right) and two sides of sacral (left/right). Serially numbered, opaque, sealed envelopes containing the frequency dose assignments and the testing condition assignments were developed by the biostatistician and included a unique, site specific randomization number, and this information was used by the research assistant who performed the tests and/or TNT study. The research assistants performing tests/treatment (XX, TP) were not involved with data and statistical analysis. Safety and tolerability assessments were formed after each treatment and during their follow up visits by a study coordinator who was blinded to the outcome results.
Statistical Analyses:
Quantitative variables are summarized using the sample average and standard error for the baseline and post-treatment measures and the difference between the two time points respectively. Since the sample sizes were too small to verify if the outcome measures are normally distributed, we used non-parametric methods for the analysis. The changes in weekly FI episodes (primary outcome) and other secondary outcomes when compared to baseline in each of the 3 treatment groups were tested using a paired Wilcoxon signed-rank test. Additionally, we tested the changes from baseline across the three treatment arms using the Kruskal-Wallis test. We compared the responder rate between the three treatment arms using a Fisher’s exact test. A nominal significance level of 5% was used throughout the analysis to determine the significance of variables. The data were analyzed using intention to treat (ITT) and in case of missing data, the last observation was carried forward. All calculations were performed using R statistical analysis software (ver. 3.5.2).
RESULTS
Demographics:
Thirty-five patients were enrolled, of whom 2 were withdrawn, one because of severe diarrhea and one due to diarrhea and personal reasons prior to randomization (Fig. 1). Thirty-three FI patients (23 females, 58.9±2.1 years) were randomized and completed at least one treatment session, and all were included in our ITT analysis. Three patients (9.1%) had diabetes mellitus, 2 patients (6.1%) had history of back injury, 3 patients (9.1%) had history of back surgery, 1 patient (3.1%) had ankylosing spondylitis, 1 patient (3.1%) had previous anal sphincteroplasty, 3 patients (9.1%) had hysterectomy, 2 (6.1%) had bladder surgery, 4 (12.1%) patients had hemorrhoid surgery, and 1 patient (3.1%) had prostate cancer with radiation treatment. The median number of pregnancies in the FI patients was 2 (range 0-5). One female patient (4.3%, 1/23) was nulliparous. Eighteen patients (78.3%, 18/23) had vaginal deliveries, 3 of whom also had C-section, while 4 (17.4%, 4/23) only had C-section. Eleven patients had vaginal delivery with tears and 6 had forceps-assisted delivery. Based on the predominant type of FI, 27.3% patients had passive FI, 39.4% patients had urge type FI and 33.3% had both passive and urge type of FI (Table 1). 8, 10 Except gender distribution, we found no differences in the demographic variables including bowel symptoms, severity or type of FI and proportion of patients with anal sphincter defects or neuropathy, between the three groups (Table 1). All patients included in the study were recruited from the Augusta site. Three patients were recruited from Manchester site (but not randomized), one had AE, one lost during screening (left city) and one declined to participate.
Table 1:
Baseline demographic data, fecal incontinence symptoms and severity and anorectal neurophysiology characteristics. (Median(IQR)) ITT population (All from Augusta site).
| 1 Hz (n = 11) | 5 Hz (n = 11) | 15 Hz (n = 11) | |
|---|---|---|---|
| Age (years) | 63.0 (13) | 59.0 (26) | 51.0 (13) |
| Female/Male | 4/7 | 6/5 | 11/0 |
| Duration of FI symptoms (y), median (Range) | 3.0 (5.0) | 2 (5.0) | 3.0 (5.0) |
| Stool frequency/week | 11.0 (7) | 13 (15) | 10.0 (8) |
| Stool consistency (BSFS)/week | 4.9 (1.9) | 4.7 (1.8) | 4.8 (1.4) |
| Severity of FI (0-3)/week | 1.5 (0.8) | 1.4 (1.0) | 1.2 (0.5) |
| FI episodes/week | 4.0 (5) | 6.0 (15) | 5.0 (5) |
| Passive incontinence, n (%) | 4 (36%) | 4 (36%) | 1 (9%) |
| Urge incontinence, n (%) | 6 (54%) | 2 (18%) | 5 (46%) |
| Mixed incontinence, n (%) | 1 (9%) | 5 (46%) | 5 (46%) |
| Anal sphincter defects (%) | 63.6% | 72.7% | 72.7% |
| Anal neuropathy, n (%) | 10/11 (90%) | 11/11 (100%) | 10/11 (90%) |
Effect of gender on baseline measurements:
Despite random assignment, we found that more men were randomized to the 1 Hz arm compared to the other 2 groups (Table 1). Therefore, we assessed whether gender had a confounding effect on the treatment effects by assessing seven different measures of FI. We found no significant differences between males and females on the duration of symptoms (p=0.5106), number of leakage events (p=0.5593), stool frequency (p=0.2221), stool consistency (p=0.3398), weekly use of pads (p=0.0557), severity of FI (p= 0.7605) and urgency (p=0.0688). Hence it is unlikely that any imbalances in gender distribution within the three treatment arms during randomization had significant effect on results.
Effects of TNT on primary outcome measure:
When compared to baseline, the number of stool leakage episodes per week significantly decreased (1 Hz, P=0.01; 5 Hz, p=0.022 and 15 Hz, p=0.007) after TNT treatment in all three groups. The 1 Hz group showed the greatest reduction in mean(95% CI) FI episodes (4.2±2.8) followed by the 15 Hz group (3.4±2.5) and the 5 Hz group (2±1.7). There was no difference between the three groups (p=0.2397) (Table 2). Also, the co-primary outcome measure, the percentage of responders (95% CI) was significantly higher (p=0.04) in the 1Hz group (90.9±9.1%, 10/11) when compared to the 5 Hz group (36.4±18.2%, 4/11) and the 15 Hz group (54.4±18.2%, 6/11), (Fig. 2). There was no difference between the 5 Hz and 15 Hz groups (p=0.66).
Table 2:
Effects of 3 different TNT frequencies on bowel and fecal incontinence symptoms and pad use. (Mean (SD)), ITT analysis.
| 1 Hz (n=11) |
5 Hz (n=11) |
15 Hz (n=11) |
|||||||
|---|---|---|---|---|---|---|---|---|---|
| Baseline | Post-treatment | Δ | Baseline | Post-treatment | Δ | Baseline | Post-treatment | Δ | |
| Primary Outcome | |||||||||
| No. of FI episodes/week | 7.1 (7.4) | 2.9 (4.3)* | −4.2 (4.7) | 11.1 (11.1) | 9.1 (9.9)* | −2.0 (2.9) | 6.1 (4.4) | 2.7 (2.6)* | −3.4 (4.3) |
| Secondary outcome | |||||||||
| Stool frequency/week | 13.3 (6.7) | 12.3 (5.6) | −1.4 (3.9) | 16.6 (13.2) | 15.6 (9.2) | −1.0 (6.7) | 10.8 (5.6) | 9.6 (3.1) | −1.2 (4.3) |
| Stool consistency/week | 4.7 (1.2) | 4.7 (1.1) | 0.01 (0.8) | 4.6 (1.3) | 4.8 (0.9) | 0.2 (1.16) | 4.7 (1.1) | 4.3 (1.0) | −0.3 (0.8) |
| Weekly use of pads | 5.1 (9.1) | 5.0 (8.0) | −0.09 (4.3) | 10.4 (15.5) | 8.7 (11.9) | −1.6 (5.2) | 6.4 (5.5) | 4.4 (4.3) | −2.0 (5.9) |
| Urgency for stooling/week | 6.8 (8.2) | 5.5 (7.2) | −1.3 (5.5) | 10.2 (9.2) | 9.6 (8.1) | −0.6 (8.1) | 4.9 (4.5) | 4.7 (3.7) | −0.2 (4.2) |
| Severity of leakage amount (0-3)/week | 1.7 (0.6) | 0.7 (0.7)* | −1.0 (0.9) | 1.6 (0.7) | 1.3 (0.9) | −0.3 (0.7) | 1.3 (0.3) | 0.7 (0.6) | −0.6 (0.8) |
P<0.05 vs. Baseline.
Figure 2.
The percentage of responders (n) in each of the three groups of FI patients.
Effects of TNT on secondary outcome measures:
The severity of the amount of stool leakage decreased only in the 1 Hz group (p=0.012) compared to baseline (Table 2). Otherwise, there were no differences in the weekly mean stool frequency, mean stool consistency, frequency of pad usage, and urgency for defecation in all groups (Table 2).
Effects of TNT on FI severity:
The SGA score decreased in the 1 Hz group (p=0.02) and 15 Hz group (p=0.01) respectively, but not in 5 Hz group (p=0.1024) (Table 3), and there were no differences between the three groups (P=0.501). There was no change in the FISI scores in either the 1Hz group (p=0.102) or 5 Hz group (p=0.108) or 15 Hz group (p=0.318). The FISS score decreased in all three groups, but was only statistically significant in the 1 Hz group (p=0.047), but not in 5 Hz group (p=0.07) and in 15 Hz group (p=0.1687). These measures indicate that the overall bowel function including severity of FI improved significantly, especially with the 1 Hz frequency when compared to baseline, but there were no differences between the three groups.
Table 3:
Effects of TNT on FI severity, and QOL domains. (Mean (SD)).
| 1 Hz (n=11) |
5 Hz (n=11) |
15 Hz (n=11) |
|||||||
|---|---|---|---|---|---|---|---|---|---|
| Baseline | Post-treatment | Δ | Baseline | Post-treatment | Δ | Baseline | Post-treatment | Δ | |
| FISS | 8.4 (2.6) | 6.5 (3.4)* | −1.9 (2.9) | 10.2 (1.9) | 9.1 (2.9) | −1.1 (2.4) | 9.0 (1.4) | 8.8 (2.4) | −0.2 (1.4) |
| FISI | 35.5 (14.9) | 27.1 (14.8) | −8.4 (15.4) | 36.8 (12.7) | 31.2 (14.6) | −5.6 (10.6) | 36.1 (6.7) | 30.8 (13.7) | −5.3 (16.7) |
| SGA (VAS) | 4.9 (1.7) | 3.5 (2.2)* | −1.4 (1.8) | 6.1 (2.8) | 5.0 (3.3) | −1.1 (2.5) | 6.1 (2.1) | 3.5 (3.3)* | --2.6 (3.2) |
| QOL-Lifestyle | 2.8 (0.8) | 2.9 (0.8) | 0.1 (0.3) | 2.7 (1.2) | 3.0 (1.0)* | 0.3 (0.4) | 2.1 (0.9) | 2.7 (1.1) | 0.6 (1.3) |
| QOL-Coping | 1.9 (0.8) | 2.3 (0.9)* | 0.4 (0.5) | 2.1 (0.9) | 2.3 (1.1) | 0.2 (0.7) | 1.6 (0.4) | 2.2 (1.0) | 0.6 (0.8) |
| QOL-Depression | 2.8 (0.9) | 3.1 (0.8)* | 0.3 (0.5) | 2.9 (0.9) | 3.3 (0.7)* | 0.4 (0.4) | 2.5 (0.9) | 2.9 (0.9) | 0.4 (0.8) |
| QOL-Embarrassment | 1.9 (0.8) | 2.4 (0.8)* | 0.5 (0.6) | 1.7 (0.7) | 2.5 (1.0)* | 0.8 (0.7) | 1.9 (0.6) | 2.6 (1.0)* | 0.7 (0.8) |
P<0.05 vs. Baseline;
FISS, fecal incontinence symptom severity; SGA, subject global assessment; VAS, visual analog scale; QOL, quality of life.
Effects of TNT on FI-QOL:
After TNT therapy, several FI-QOL domains significantly improved in all 3 groups. Patients in the 1 Hz and 5 Hz groups showed the greatest changes with regards to an improvement in at least 3 QOL domains (coping, depression, life-style and embarrassment), whereas in the 15 Hz group there was improvement in only one domain (Table 3).
Effects of TNT on anorectal manometry, rectal sensation and compliance:
The anal squeeze pressure and the sustained squeeze pressure increased in the 1 Hz group when compared to either baseline (p<0.01) or the other two groups (p=0.04), but there were no changes in the 5 Hz and 15 Hz groups (Table 4). Also, the rectal sensory thresholds for constant sensation, urge to defecate, and the maximal tolerable volume increased (p<0.05) in the 1 Hz group, but there were no significant changes in the 5 Hz or 15 Hz groups, and between the three groups (Table 4). The rectal compliance (dv/dp) improved (p<0.05) only in the 1 Hz group when compared to baseline, but not between groups, or in the 5 Hz and 15 Hz groups (Table 4).
Table 4:
Effects of 3 different TNT frequencies on anal sphincter function, rectal sensation and rectal compliance as assessed by changes in intrarectal pressure during incremental rectal distension. (Mean (SD)).
| 1 Hz (n=11) |
5 Hz (n=11) |
15 Hz (n=11) |
||||
|---|---|---|---|---|---|---|
| Baseline | Post-treatment | Baseline | Post-treatment | Baseline | Post-treatment | |
|
| ||||||
| Resting Pressure (mmHg) | 54.7 (21.4) | 68.4 (29.9) | 65.5 (33.8) | 71.5 (36.8) | 55.3 (23.5) | 58.9 (18.4) |
| Maximal Squeeze Pr. (mmHg) | 113.2 (27.9) | 176.7 (55.4)** | 156.7 (128.1) | 172.7 (115.3) | 111.4 (60.5) | 141.2 (116.8) |
| Sustained Squeeze Pr (mmHg) | 66.5 (25.6) | 87.2 (30.3)* | 100 (93.8) | 94.2 (68.2) | 67.3 (34.8) | 71.4 (33.6) |
| First sensation (ml) | 15.5 (6.9) | 18.2 (7.5) | 20.0 (8.9) | 25.4 (17.5) | 14.6 (6.9) | 13.6 (5.1) |
| Constant sensation (ml) | 31.8 (14.7) | 64.6 (54.1)* | 36.4 (16.3) | 52.7 (26.8) | 28.2 (18.3) | 36.4 (14.3) |
| Desire to defecate (ml) | 98.2 (89.9) | 125.5 (67.1) | 74.6 (30.8) | 81.8 (38.2) | 60.9 (37.3) | 55.5 (17.5) |
| Urge (ml) | 143.6 (94.7) | 189.1 (65.9)* | 102 (37.6) | 131.8 (57.8) | 90.9 (49.1) | 85.5 (27.7) |
| MTV (ml) | 162.3 (89.6) | 225.3 (63.5)* | 107 (40.8) | 163.6 (77.6) | 96.7 (46.4) | 103.6 (33.8) |
|
| ||||||
| Rectal distending volume | Rectal pressure (mmHg) | |||||
|
| ||||||
| 20 ml | 20.6 (15.5) | 10.4 (12.3)* | 19.8 (10.3) | 20.6 (21.4) | 27.0 (19.9) | 22.7 (20.1) |
| 40 ml | 33.3 (14.3) | 22.9 (11.7)* | 33.4 (13.7) | 30.7 (13.5) | 41.7 (14.8) | 31.3 (9.7) |
| 70 ml | 33.8 (13.0) | 22.7 (11.6)* | 38.7 (18.2) | 33.3 (23.0) | 49.5 (22.3) | 36.3 (9.6) |
| 100 ml | 40.8 (12.6) | 24.6 (15.5)** | 35.9 (11.5) | 25.2 (13.3) | 45.0 (10.0) | 42.8 (12.4) |
P<0.05 vs. Baseline
P<0.005 vs Baseline;
ARM, anorectal manometry; Pr= pressure; MTV, maximal tolerable volume.
Effects of TNT on anorectal neuropathy:
The latencies for the lumbo-anal and sacro-anal MEPs were prolonged when compared to historical healthy controls8, 10 in all 3 groups at baseline (1 Hz, P< 0.0001; 5 Hz, p<0.001 and 15 Hz, p<0.001), indicating anal neuropathy. The baseline MEP latencies were not significantly different between groups. After TNT, the bilateral lumbo-anal and sacro-anal MEP latencies were shortened in the 1 Hz group (p<0.025), but only the right side sacro-anal MEP in the 5 Hz group, and bilateral lumbo-anal latencies in the 15 Hz group (Table 5). After TNT, only right side lumbo-rectal MEP latency decreased (p=0.025) in the 1 Hz and right side sacro-rectal in the 5 Hz group (p=0.044), but no changes in the 15 Hz group and at other rectal sites (Table 5). There were no differences between the three groups.
Table 5:
Effects of 3 different TNT frequencies on anal and rectal neuropathy as assessed by bilateral lumbar and sacral MEPs. (Mean (SD)).
| 1 Hz (ms) |
5 Hz (ms) |
15 Hz (ms) |
||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Baseline | Post-treatment | Δ | Baseline | Post-treatment | Δ | Baseline | Post-treatment | Δ | ||
| Left | Lumbo-anal | 5.1 (1.6) | 3.8 (0.9)* | −1.3 (1.6) | 6.1 (2.1) | −0.5 (1.1) | −0.5 (1.1) | 5.4 (2.5) | −1.4 (2.2) | −1.4 (2.2) |
| Lumbo- rectal | 3.1 (1.1) | 2.7 (0.5) | −0.4 (1.1) | 4.5 (1.7) | 3.4 (0.8) | 1.1 (2.3) | 3.8 (1.2) | 4.0 (1.0) | 0.2 (1.6) | |
| Right | Lumbo-anal | 5.3 (1.3) | 3.9 (0.8)* | −1.4 (1.5) | 6.1 (1.7) | 5.2 (1.5) | −0.9 (1.4) | 5.9 (2.2) | 4.4 (1.4)* | −1.5 (2.1) |
| Lumbo-rectal | 3.9 (1.3) | 3.0 (0.6)* | −0.9 (0.9) | 4.6 (2.4) | 3.9 (0.8) | −0.6 (2.4) | 3.7 (0.9) | 3.8 (1.0) | 0.1 (1.4) | |
| Left | Sacro-anal | 4.9 (1.2) | 3.8 (0.9)* | −1.1 (1.5) | 6.0 (1.6) | 5.0 (1.4) | −1.0 (1.7) | 4.9 (1.9) | 4.4 (2.4) | −0.5 (3.3) |
| Sacro-rectal | 3.3 (0.9) | 3.0 (0.7) | −0.3 (0.7) | 5.3 (1.7) | 4.1 (1.4) | −1.2 (1.9) | 4.0 (1.4) | 3.7 (1.5) | −0.3 (0.5) | |
| Right | Sacro-anal | 5.3 (1.6) | 3.7 (1.2)* | −1.6 (2.0) | 5.7 (1.9) | 4.5 (1.4)* | −1.2 (1.7) | 5.7 (2.1) | 4.7 (1.6) | −1.0 (2.4) |
| Sacro-rectal | 3.8 (1.1) | 3.3 (0.7) | −0.5 (0.8) | 5.0 (2.6) | 3.4 (0.8)* | −1.5 (2.2) | 4.7 91.6) | 3.6 (1.3) | −1.1 (2.1) | |
P<0.05 vs. Baseline
Adverse events, safety and tolerability:
There were 9 adverse events including 3 serious adverse events (Table 6). One adverse event was adjudicated as study related. A patient with chronic back pain reported worsening back pain, tingling and numbness in legs for one day that subsided and patient completed all 6 sessions. The serious adverse events requiring hospitalization were, fracture pelvis (1), gastrointestinal bleed secondary to the use of non-steroidal anti-inflammatory drug (1), and pneumonia (1). Other adverse events were hand skin discoloration (1), kidney stone (1), transient hand tingling and numbness (1), 5th metatarsal fracture (1), and joint pains (1). None of the above were considered device related.
Table 6:
Number of subjects with adverse events.
| Adverse events | 1 Hz | 5 Hz | 15 Hz |
|---|---|---|---|
| Fracture pelvis (withdrawn before randomization) | |||
| GI bleed secondary to NASIDS | 1 | ||
| Pneumonia | 1 | ||
| Skin discoloration | 1 | ||
| Kidney stone | 1 | ||
| Transient hand tingling and numbness | 1 | ||
| 5th metatarsal fracture | 1 | ||
| Joint pains | 1 | ||
| Back pain, leg tingling & numbness | 1 |
DISCUSSION
Current treatments for FI remain unsatisfactory with approximately one half of patients achieving acceptable continence.16,25–33 Moreover, previous studies have not systematically examined anorectal sensorimotor function, rectal capacity, anorectal neuropathy and symptom severity in FI, especially after therapeutic interventions. Many studies have reported improvement based on subjective endpoints such as adequate relief of symptoms34,35 without objective appraisal of outcomes. Of relevance, we have previously shown that temporary SNS decreases corticoanal excitability alongside improvements in FI symptoms but without changes in anorectal manometry.14 Here, we aimed to not only examine the effects of a novel, non-invasive therapy on FI symptoms but also to objectively evaluate the scientific basis for this therapy by evaluating manometric findings and neurophysiological changes.
We found that TNT at all three frequencies significantly decreased the number of FI episodes per week when compared to baseline (primary outcome), although there was no difference between the 3 groups. There were greater numbers of responders in the 1 Hz group when compared with the 5 Hz and 15 Hz groups. Although there was some improvement in patients who received the 5 and 15 Hz frequencies, their effects were less pronounced than 1 Hz. These findings indicate that TNT is a useful treatment modaltity and that the 1 Hz frequency is a viable option for improving FI symptoms and restoring continence.
These 1 Hz centered changes were further substantiated by improvements in the severity of fecal incontinence as assessed by several scales. The SGA which assesses a global improvement in the severity of FI on a VAS, and the FISS which is an index based on the aggregate of multiple FI symptoms improved. Also, the FI-QOL a validated FI specific instrument showed clinically meaningful 20 improvements in several key domains such as the coping /behavior skills, and feelings of embarrassment, and feelings of depression and self-perception and improvements in life style. Thus, both the FI severity and its effects on QOL, which are major issues in these patients improved substantially with TNT therapy.
The subjective improvements in symptoms were also matched by improvements in neuropathy and anorectal physiology. We found that the bilateral lumbar and sacral anal neuropathy in patients with FI significantly improved as evidenced by the shortening of anal MEP latencies with the 1 Hz frequency. There were lesser degrees of improvement in the anal neuropathy with either the 5 Hz or 15 Hz frequency. This observation supports the notion that TNT improves bowel function possibly by improving the underlying neuropathy. It is likely that TNT induces neuroplasticity – the inherent ability of the neurons to adapt and change – and thereby alters the excitability in the motor neurons of the spinal cord, improving nerve conduction. However, this requires validation through direct recordings of the spinal cord.
We also observed significant improvements in anorectal sensori-motor physiology. The squeeze and sustained squeeze pressures improved especially with 1 Hz frequency indicating that improved neuronal function also led to improved anal sphincter muscle function. Likewise, the rectal sensory thresholds and the rectal capacity also improved. It is likely that improvements in rectal sensation were in part due to improvement in rectal compliance. These findings suggest that TNT produces a multidimensional effect that leads to improvement in both symptoms and the underlying pathophysiology of FI.
The limitations of our study include the small number of subjects enrolled in each arm of the study; but it is important to recognize that this was both feasibility and optimal magnetic frequency assessment study, and not a full phase III RCT. Also, this was not a sham-controlled study, but the sample was adequate to provide promising data supporting this treatment approach. Although our subjects were randomized , there were more men in the 1 Hz arm of our study, and gender did not significantly influence the outcome of our study. However unlikely, TNT may be more efficacious in men, and a future gender matched study is needed to addres this aspect. Here we tested 3 frequencies and it is possible that others may also have physiological effects. Previous studies have suggested that higher frequency magnetic stimulation is more effective for delayed conduction and neuropathies especially in the CNS.36 Also, one lumbosacral study showed that the 15 Hz frequency increased cortical excitability compared to 5 Hz, but 1 Hz was not tested, so that might explain a difference.13 By contrast in another study, the 1 Hz lumbosacral stimulation did alter spinal responses.37 So, it might be that low frequencies are more effective in the peripheral neural circuitry – such as spinal cord and peripheral nerves. However, whether other lower frequencies such as 2 or 3 Hz are also effective is unclear. Likewise, we tested our subjects with a fixed dose of 2400 magnetic stimulations, and whether a higher dose such as 3600 or a lower dose such as 1800 is equally or more effective is unknown. A sham-controlled, longer duration study with a larger sample size is needed to establish the efficacy of TNT, since FI is a chronic problem.
In conclusion, our study showed that TNT improves bowel function and FI episodes in the short-term, especially with the 1 Hz frequency, alongside improvements in anorectal neuropathy and anorectal sensori-motor function. These findings suggest that TNT is a safe and promising novel treatment for FI.
Supplementary Material
What is known
Fecal incontinence (FI) affects 10% of the population, and there are inadequate randomized controlled trials that show efficacy or mechanistic understanding of non-invasive treatments.
Although anorectal neuropathy is a significant pathophysiological mechanism for FI, there has been no treatment for this dysfunction.
Neuromodulation therapy using repetitive magnetic stimulation has been shown to induce neuroplasticity and improve neuropathy in neurological disorders.
What is new here
We examined the usefulness of a new treatment approach, Translumbosacral Neuromodulation Therapy (TNT), and found that it improves FI symptoms and the underlying mechanism(s) of FI including neuropathy, and quality of life.
The effects were most pronounced with the 1 Hz frequency when compared to others.
TNT was efficacious in improving FI symptoms and the underlying pathophysiology.
Acknowledgement:
This work was supported by NIH grant 5R21 DK104127-02. We sincerely acknowledge the expert research assistance of Mrs. Amanda Schmeltz, Mrs. Meagan Gibbs O’banion, Ms. Ijeoma Azih, Ms. Shashana Fiedler, and statistical analysis support of Mrs. Patricia Hall. We also appreciate the technical assistance provided by Dr. K. Rattanakovit and Dr. ML. Harris for the conduct of the study. Importantly, we thank Mrs. Helen Smith for her superb secretarial assistance.
Footnotes
Conflicts of Interest: All authors declare no conflicts of interests with this study.
ClinicalTrials.Gov: Registered at Clinicaltrials.gov no NCT02556151
References:
- 1.Whitehead WE, Borrud L, Goode PS, et al. Fecal incontinence in US adults: epidemiology and risk factors. Gastroenterology 2009;137:512–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Ditah I, Devaki P, Luma HN, et al. Prevalence, trends, and risk factors for fecal incontinence in United States adults, 2005-2010. Clin Gastroenterol Hepatol 2014;12:636–43. [DOI] [PubMed] [Google Scholar]
- 3.Leung FW, Rao SS. Fecal incontinence in the elderly. Gastroenterol Clin North Am 2009;38:503–11. [DOI] [PubMed] [Google Scholar]
- 4.Leung FW, Schnelle JF. Urinary and fecal incontinence in nursing home residents. Gastroenterol Clin North Am 2008;37:697–707. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Dunivan GC, Heymen S, Palsson OS, et al. Fecal incontinence in primary care: prevalence, diagnosis, and health care utilization. Am J Obstet Gynecol 2010;202:493.e1–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Rao SS, Patel RS. How useful are manometric tests of anorectal function in the management of defecation disorders? Am J Gastroenterol 1997;92:469–75. [PubMed] [Google Scholar]
- 7.Bharucha AE, Rao SS. An update on anorectal disorders for gastroenterologists. Gastroenterology 2014;146:37–45. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Rao SS, Coss-Adame E, Tantiphlachiva K, et al. Translumbar and transsacral magnetic neurostimulation for the assessment of neuropathy in fecal incontinence. Dis Colon Rectum 2014;57:645–52. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Tantiphlachiva K, Attaluri A, Valestin J, et al. Translumbar and transsacral motor-evoked potentials: a novel test for spino-anorectal neuropathy in spinal cord injury. Am J Gastroenterol 2011;106:907–14. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Xiang X, Patcharatrakul T, Sharma A, et al. Cortico-anorectal, Spino-anorectal, and Cortico-spinal Nerve Conduction and Locus of Neuronal Injury in Patients With Fecal Incontinence. Clin Gastroenterol Hepatol 2019;17:1130–1137. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Rao SSC. Pathophysiology of adult fecal incontinence. Gastroenterology 2004;126:S14–22. [DOI] [PubMed] [Google Scholar]
- 12.Rao S, Erdogan A, Coss-Adame E, et al. Repetitive Translumbar Magnetic Stimulation (rTLMS) and Transsacral Magnetic Stimulation (rTSMS): a novel treatment for Levator Ani Syndrome (LAS). Am J Gastroenterol 2013;108:S182. [Google Scholar]
- 13.Harris ML, Singh S, Rothwell J, et al. Rapid rate magnetic stimulation of human sacral nerve roots alters excitability within the cortico-anal pathway. Neurogastroenterol Motil 2008;20:1132–9. [DOI] [PubMed] [Google Scholar]
- 14.Sheldon R, Kiff ES, Clarke A, et al. Sacral nerve stimulation reduces corticoanal excitability in patients with faecal incontinence. Br J Surg 2005;92:1423–31. [DOI] [PubMed] [Google Scholar]
- 15.Griffin KM, Pickering M, O’Herlihy, et al. Sacral nerve stimulation increases activation of the primary somatosensory cortex by anal canal stimulation is an experimental model. BJS 2011;98:1160–69. [DOI] [PubMed] [Google Scholar]
- 16.Rao SS, American College of Gastroenterology Practice Parameters C. Diagnosis and management of fecal incontinence. American College of Gastroenterology Practice Parameters Committee. Am J Gastroenterol 2004;99:1585–604. [DOI] [PubMed] [Google Scholar]
- 17.Yan Y, Xiang X, Sharma A, et al. Validation of a prospective stool diary instrument for assessment of fecal incontinence. Gastroenterology 2019;156:S-355. [Google Scholar]
- 18.Rockwood TH, Church JM, Fleshman JW, et al. Patient and surgeon ranking of the severity of symptoms associated with fecal incontinence: the fecal incontinence severity index. Dis Colon Rectum 1999;42:1525–32. [DOI] [PubMed] [Google Scholar]
- 19.Bharucha AE, Locke GR, Seide BM, et al. A new questionnaire for constipation and faecal incontinence. Aliment Pharmacol Ther 2004;20:355–64. [DOI] [PubMed] [Google Scholar]
- 20.Rockwood TH, Church JM, Fleshman JW, et al. Fecal Incontinence Quality of Life Scale: quality of life instrument for patients with fecal incontinence. Dis Colon Rectum 2000;43:9–16. [DOI] [PubMed] [Google Scholar]
- 21.Rao SSC, Hatfield R, Leistikow J, Soffer E, Conklin J. Manometric tests of anorectal function in healthy humans. Am J Gastroenterol 1999; 94: 773–83. [DOI] [PubMed] [Google Scholar]
- 22.U. S. Food and Drug Administration/Center for Devices and Radiological Health. Class II special controls guidance document: Repetitive Transcranial Magnetic Stimulation (rTMS) Systems - Guidance for Industry and FDA Staff. 2011. [Google Scholar]
- 23.Bedard K, Heymen S, Palsson OS, et al. Relationship between symptoms and quality of life in fecal incontinence. Neurogastroenterol Motil 2018;30.doi: 10.1111/nmo.13241. Epub 2017 Nov 2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Rao SS, Azpiroz F, Diamant N, et al. Minimum standards of anorectal manometry. Neurogastroenterol Motil 2002;14:553–9. [DOI] [PubMed] [Google Scholar]
- 25.Tjandra JJ, Chan MK, Yeh CH, et al. Sacral nerve stimulation is more effective than optimal medical therapy for severe fecal incontinence: a randomized, controlled study. Dis Colon Rectum 2008;51:494–502. [DOI] [PubMed] [Google Scholar]
- 26.Michelsen HB, Thompson-Fawcett M, Lundby L, et al. Six years of experience with sacral nerve stimulation for fecal incontinence. Dis Colon Rectum 2010;53:414–21. [DOI] [PubMed] [Google Scholar]
- 27.Omar MI, Alexander CE. Drug treatment for faecal incontinence in adults. Cochrane Database Syst Rev 2013:CD002116. doi: 10.1002/14651858.CD002116.pub2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Bleier JI, Kann BR. Surgical management of fecal incontinence. Gastroenterol Clin North Am 2013;42:815–36. [DOI] [PubMed] [Google Scholar]
- 29.Graf W, Mellgren A, Matzel KE, et al. Efficacy of dextranomer in stabilised hyaluronic acid for treatment of faecal incontinence: a randomised, sham-controlled trial. Lancet 2011;377:997–1003. [DOI] [PubMed] [Google Scholar]
- 30.Boyle DJ, Murphy J, Gooneratne ML, et al. Efficacy of sacral nerve stimulation for the treatment of fecal incontinence. Dis Colon Rectum 2011;54:1271–8. [DOI] [PubMed] [Google Scholar]
- 31.Tan E, Ngo NT, Darzi A, et al. Meta-analysis: sacral nerve stimulation versus conservative therapy in the treatment of faecal incontinence. Int J Colorectal Dis 2011;26:275–94. [DOI] [PubMed] [Google Scholar]
- 32.Maeda Y, Lundby L, Buntzen S, et al. Outcome of sacral nerve stimulation for fecal incontinence at 5 years. Ann Surg 2014;259:1126–31. [DOI] [PubMed] [Google Scholar]
- 33.Whitehead W, Rao SSC, Lowry A, et al. Treatment of fecal incontinence: State-of-the-Science summary for the National Institute of Diabetes and Digestive and Kidney Disease Workshop. Am J Gastroenterol 2015;110(1):138–46. Epub 2014 Oct 21. [DOI] [PubMed] [Google Scholar]
- 34.Rao SS. Endpoints for therapeutic interventions in faecal incontinence: small step or game changer. Neurogastroenterol Motil 2016;28:1123–33. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Noelting J, Zinsmeister AR, Bharucha AE. Validating endpoints for therapeutic trials in fecal incontinence. Neurogastroenterol Motil 2016;28:1148–56. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Perera T, George MS, Grammer G, et al. The Clinical TMS Society Consensus Review and Treatment Recommendations for TMS Therapy for Major Depressive Disorder. Brain Stimul 2016;9:336–346. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Algladi T, Harris M, Whorwell PJ, et al. Modulation of human visceral sensitivity by noninvasive magnetoelectrical neural stimulation in health and irritable bowel syndrome. Pain 2015;156:1348–56. [DOI] [PubMed] [Google Scholar]
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