Introduction
Approximately 1 % of adults suffer from uncontrolled loss of stool [
1,
2]. Very few guidelines for managing fecal incontinence in adults are available, and one of these was issued by the National Institute for Health and Clinical Excellence for UK in 2007 [
3]. In general, the first-line therapy may try to solidify liquid stools with fiber elements or medications [
4]. The specialized management usually applies nonsurgical methods, such as pelvic floor exercises (PFE), biofeedback (BF), and electrical stimulation (ES) [
3], to improve the strength and coordination of the sphincter muscles. However, the internal anal sphincter consists of smooth muscles and is not amenable to voluntary exercises. Furthermore, it is difficult to actively reach the slow-twitch type I fibers [
5,
6]. It thus makes sense to use ES on the smooth and slow muscular components.
When judging the efficacy of the ES treatment or the combination of BF and ES (BF + ES), current type, current strength, and application mode are essential [
6‐
10], as recently discussed by Schwandner et al. [
11].
For example, Telford and colleagues [
5] demonstrated that the motorical threshold for sphincter muscles with low-frequency electrical stimulation (LFS) is around 20 mA. Specifically, they used the strength-duration test to measure the current strength required for visible muscle contraction at different pulse durations. They first found that the current intensity at 1 ms pulse duration was the best predictor of incontinence [
5]. Furthermore, in their control group [
12], they observed that a currency of 18.2 mA (90 % reference interval ≥19 mA) was required at 1 ms pulse duration for muscle contraction.
LFS, as used in most studies of fecal incontinence, can be very painful when applied to the pelvic floor exercises [
13‐
15], and it can cause adverse device effects (ADE) [
13]. Surprisingly, this relationship between pulse configuration, voltage amplitudes, and physiological outcome has not been addressed in any of the systematic reviews on ES for fecal incontinence, although it is well known in biomedical engineering [
6‐
10]. It was also neglected in some two-group randomized trials where two ES stimulations were compared and both ES were below the threshold for effectiveness [
13]. Stimulation with alternating current at medium frequency (MF > 1,000 Hz; amplitude-modulated medium frequency: AM-MF), also termed pre-modulated interferential ES in the literature, does not have the disadvantage of LFS because its biological effect is based on a different principle than the all-or-nothing effect of LFS [
16]. Previous systematic reviews [Supplementary Table S
1;
17‐
19] did not distinguish between LFS and MF therapies.
The systematic reviews focused either on ES [
17] or on BF [
18,
19], but they did not consider ES + BF to be a combination therapy which would be important for treatment guidelines. Here, we aim at identifying the best second-line conservative treatment, consisting in BF, ES, or BF + ES by taking into account the type, strength, and application mode of current. We specifically address duration–response relationships which were not correctly reported in previous reviews [
19] and safety issues. By finally grading the evidence [
20], we provide valuable aid to decision making in a guideline for fecal incontinence.
Methods
The protocol to this systematic review was published in PROSPERO (CRD42011001334) on June 1, 2011. A detailed description of the methods can be found in the
Electronic supplementary material. In brief, we included randomized controlled parallel-group trials of BF or ES or BF + ES in adults in need of a second-line conservative treatment and no obvious need for surgery for fecal incontinence reporting patient-related outcome, i.e., remission, response, or disease-related quality of life (QoL) on validated scales as assessed by two reviewers in consensus. Data extraction followed recommendations of the
Cochrane Handbook for Systematic Reviews of Intervention [
21]; for details, see
Electronic supplementary material.
Excluded studies and reasons for exclusion are summarized in Supplementary Table S
2. Supplementary Tables S
3 and S
4 provide details on populations, interventions, comparator, outcome, and design of included studies to find matching entries for meta-analysis. Safety issues were coded as serious adverse events (SAE) and adverse device effects (ADE), both according to ISO 14155:2011.
The 2 × 2 treatment scheme has been analyzed using an analysis of variance meta-analysis (meta-ANOVA) [
22] for the endpoint remission using the relative risk (RR) as effect measure. Results were graded high, moderate, or low quality using the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) [
20].
Discussion
Following up on promising results of the combination of ES with BF, this systematic review revealed more, high-quality evidence than previous reviews because of the publication of several new trials [
11,
14‐
16,
70‐
72,
87]. The clinical development of BF and ES can be grouped into three general phases. In the first phase, diverse case series were reported, and those had to be excluded from this systematic review.
In the second phase, narrow patient populations were studied. Specifically, fecal incontinence in younger females after delivery was considered in several trials [
70,
73‐
75]. Outcome measures included patient diary and manometry. While manometry does not adequately reflect treatment response [
16], diaries were incomplete with missing data as high as 39 % [
18]. To avoid missing data in questionnaires, patients are nowadays asked about continence/incontinence in the recent past, such as the preceding week or month.
In the third phase, several RCTs studied the intensity, duration, and the mode of BF and ES treatments. BF was given optically or acoustically, signaling change in pressure, in electromyogram (EMG) or ultrasound. EMG devices for home use were developed so that daily sessions at home were added to sessions with a therapist. ES used different frequencies and current strengths. Such “dose finding” sometimes required more than two treatment groups. The studies tended to be small so that not all comparisons were significant. The combination BF + ES was studied in recent RCTs of higher quality, which included sufficiently large numbers of patients, investigated several patient relevant endpoints at the final follow-up and also reported changes over time.
Two high-quality RCTs showed a consistently efficacious combination of AM-MF ES plus EMG-BF with 50 % patients being continent after 6 or 9 months of treatment. This treatment was consistently superior to low-frequency ES and to BF alone.
Two important aspects need to be addressed in future studies on fecal incontinence. First, an in-depth discussion on primary patient-relevant endpoint to be used is required. Specifically, Norton [
88] argued that QoL should be the primary outcome. We do not agree with her conclusion. If the aim is to treat patients suffering from fecal incontinence, a successful treatment needs to make a patient continent. The degree of incontinence measured using a validated score, such as the CCS is semiquantitative and requires fewer study subjects than the dichotomous continent/incontinent endpoint. However, it is difficult to measure continence reliably because of different patient perceptions.
QoL is an important patient-related endpoint. If QoL is assessed in an elderly population suffering from fecal incontinence, the constructs determining their QoL need to be assessed reliably. For example, the fecal incontinence QoL questionnaire enquires sexual activities, traveling by plane or train, or eating out [
89]. Patients seen in our own studies stated that these activities were not determining their QoL. The most important restrictions for their life was the personal stress caused by fecal incontinence, an important aspect was that whatever they did, the toilet had to be within reach [
90]. There is a clear need for developing a reliable and valid QoL instrument for an elderly population suffering from fecal incontinence.
Remissions and responses were more frequent the longer the therapy lasted. This was demonstrated within two trials of highest quality and across trials. In consequence, both individual results and the synthesis could be graded higher.
In their recent systematic review, Norton and Cody [
19] stated “No study reported any adverse events or deterioration in symptoms, …”. According to this systematic review, this statement needs to be corrected. Although reporting of safety was scarce, there were trials with SAEs, such as mortality, and even ADEs were reported in seven of 13 trials. Deterioration of symptoms was commonly reported as mean changes with standard deviations indicating a considerable proportion of changes for the worse. Specifically, [
11] explicitly reported deterioration in 10.3 % under AM-MF ES plus EMG-BF and 82.9 % for LFS.
In their systematic review, Hosker and colleagues [
17] stated that “electrical stimulation can cause a tissue reaction at the site of the electrodes. This usually resolves speedily when stimulation is stopped.” This statement is in line with the findings of [
11] who reported that approximately half of the patients receiving LFS treatment complained of pain during stimulation, and a quarter could not tolerate high currents required to reach the motor threshold. Some patients reported a feeling of pressure that persisted for hours after training. But these side effects in the trial were only minor ones due to thorough precautions which are not taken for granted in daily practice.
In separate work, we showed [
13] that ADEs can occur with some devices. A major concern is the danger of tissue damage at the electrode/tissue interface. This is described in detail in the Supplementary Text 3 of the
Electronic supplementary material.
Using the GRADE approach, we graded the quality of the trials and summarized the evidence (Table
3). In their recent review, Norton and Cody [
19] stated that “treatment options for fecal incontinence have not yet been investigated by means of well-designed trials.” The result of our systematic review is different. We have identified three well-designed randomized controlled trials of high quality [
11,
72,
77] and another three trials of medium quality and sufficient ES [
14,
18,
73].
Table 3
GRADE evidence profile of 5 trials investigating electrical stimulation plus biofeedback (ES + BF) combinations
Positively continent among the randomized (follow-up up to 9 months) |
4 | No serious limitations | No serious inconsistency | No serious indirectness | Seriousa
| Strong associationb Dose response gradientc
| ⊕ ⊕ ⊕ ⊕ High | Critical |
Disease severity (follow-up up to 3 months; measured with: Cleveland Clinic score) |
4d
| No serious limitations | No serious inconsistency | No serious indirectness | Seriousa
| Dose response gradientc
| ⊕ ⊕ ⊕ ⊕ High | Critical |
Disease score (follow-up up to 6 months; assessed with: modified Vaizey Score) |
2 | No serious limitations | No serious inconsistency | No serious indirectness | Seriousa
| Dose response gradientc
| ⊕ ⊕ ⊕ ⊕ High | Critical |
Resting pressure (follow-up up to 3 months; measured with: manometry) |
4 | Seriouse
| Seriouse
| No serious indirectness | Seriousf
| Dose response gradientg
| ⊕⊕○○ Low | Not important |
Squeeze pressure (follow-up up to 3 months; measured with: manometry) |
4 | Seriouse
| Seriouse
| No serious indirectness | Seriousf
| Dose response gradientg
| ⊕⊕○○ Low | Not important |
One limitation of this review is that observational studies were excluded. Such quasi-randomized studies were considered as evidence of safe treatments involving properly working devices rather than evidence of efficacy. Furthermore, trial registries did not cover all trials before the 2008 version of the Declaration of Helsinki.
Despite these limitations, this systematic review is the first considering BF and ES to be a combination therapy, and in a supplementary analysis LFS was distinguished from AM-MF ES. An overview of the component treatments, their respective duration and intensity gradients is provided. Endpoints were weighted by grade of evidence to embed and support the results of pivotal trials. A first survey of safety is provided and discussed.