Electrical stimulation of the lower esophageal sphincter may be an effective method of restoring the antireflux of the lower esophageal sphincter in gastroesophageal reflux disease patients. Early results from clinical trials show that implantation of a device that delivers electrical stimulation to the lower esophageal sphincter is safe and can significantly improve GERD symptoms, reduce dependency on medication, and improve esophageal acid exposure levels over the long term without side effects. However, larger and blinded randomized controlled trials are still needed to confirm these preliminary findings and to establish the generalizability of the results.

1. 189ISSN 1747-4124© 2013 Expert Reviews Ltd10.1586/EGH.13.1www.expert-reviews.com
Editorial
Gastroesophageal reflux disease (GERD)
is the leading diagnoses for gastro­intestinal
disorders in outpatient clinic visits in the
USA and has a rising worldwide preva-
lence [1–3]. It has significant impact on
patients’ quality of life, resulting in sig-
nificant healthcare resource utilization [4].
Acid suppression, particularly with proton
pump inhibitors (PPIs), is highly effective
in controlling the symptoms and compli-
cations of GERD [5]. However, current
pharmacologic therapy targets acid secre-
tion rather than the underlying patho-
physiology of GERD, which may result in
persisting symptoms and reduced quality
of life, despite pharmacologic therapy [6].
Inadequate control of symptoms and rising
concerns about the long-term safety and
cost of medications have been the main
reasons for choosing surgical therapy for
GERD [7]. Fundoplication is effective, but
is associated with adverse effects [7]. This
unmet medical need has led to multiple
attempts at development of less-invasive
endoscopic and surgical therapies for the
treatment of GERD [8].
EndoStim™ lower esophageal sphinc-
ter (LES) stimulation system (EndoStim,
The Hague, The Netherlands) is an
implantable electrical stimulator that
delivers electrical stimulation therapy to
the LES. It is similar to traditional neuro­
stimulators with three components; a
bipolar stimulation lead with two stitch
electrodes, an implantable pulse generator
(IPG) and an external programmer. The
IPG and stimulation leads are implanted
by conventional laparoscopy into the mus-
cle of the lower esophageal body. The lead
is delivered through the abdominal wall
and secured to the IPG located in a sub-
cutaneous pocket in the left upper quad-
rant. Following implantation, a wireless
programmer is used to interrogate and
program the IPG.
Electrical stimulation of the LES in ani-
mal models has been shown to increase
resting LES pressure [9–11]. Short-term LES
electrical stimulation, using temporary
leads implanted in the LES in subjects with
GERD, has supported observations from
animal studies. Importantly, LES stimula-
tion did not interfere with normal swallow
functions, such as LES relaxation, and was
not associated with any sensation or side
effects. These observations suggest that
electrical stimulation of the LES may be an
effective method of restoring the antireflux
of the LES in GERD patients [12,13].
Rodriguez et al. conducted an open-
label trial of LES stimulation in 24 chronic
GERD patients seeking alternative therapy
for their GERD [14]. All patients were at
least partially responsive to acid suppres-
sion therapy with PPI. The trial included
patients with GERD symptoms for a
Implanted electrical devices and
gastroesophageal reflux disease: an
effective approach to treatment
Expert Rev. Gastroenterol. Hepatol. 7(3), 189–191 (2013)
“Inadequate control of symptoms and rising concerns about the
long-term safety and cost of medications have been the main
reasons for choosing surgical therapy for gastroesophageal
reflux disease.”
Keywords: electrical stimulation • gastroesophageal reflux disease • gastroesophageal reflux disease
treatment • implantable stimulator • lower esophageal sphincter • lower esophageal sphincter
stimulation • medical devices • stimulator
Michael D Crowell
Division of Gastroenterology
and Hepatology, Mayo Clinic,
13400 East Shea Boulevard,
Scottsdale, AZ 85259, USA
Tel.: +1 480 301 6990
Fax: +1 480 301 6737
crowell.michael@mayo.edu
For reprint orders, please contact reprints@expert-reviews.com

2. 190 Expert Rev. Gastroenterol. Hepatol. 7(3), (2013)
Editorial
median of 8 years and chronic PPI medication use for more than
6 years. Gastroesophageal reflux was documented using esophageal
pH testing. Patients with hiatal hernia greater than 3 cm or long
segment Barrett’s were excluded. At 1 year, their median GERD–
Health-Related Quality of Life (GERD–HRQL) scores improved
significantly with LES electrical stimulation compared to baseline
GERD–HRQL scores on‑PPI (9 vs 2; p = 0.002) and off-PPI (23.5
vs 2; p < 0.001). GERD–HRQL sleep and dysphagia scores also
improved significantly. Frequency and severity of heartburn and
regurgitation and of nocturnal symptoms improved significantly
over time with LES electrical stimulation. At baseline, 33% of on-
PPI and 88% of off-PPI patients reported that reflux impacted their
sleep. Bothersome dysphagia due to reflux was reported by 13% of
on-PPI and 58% of off-PPI patients. At the 12-month follow-up,
only 4% of the patients reported bothersome impact of GERD on
sleep (p = 0.001 vs on-PPI; p < 0.001 vs off-PPI) and bothersome
dysphagia/odynophagia (p = 0.3 vs on-PPI; p = 0.001 vs off-PPI).
All but one patient (96%) reported complete cessation of their PPI
use. There was significant and sustained improvement in patients’
median 24-h distal esophageal acid exposure at 1 year (10.1 vs 3.3;
p < 0.001) compared with their baseline. Normalization, or at least
a 50% reduction in distal esophageal acid exposure, was observed
in 77% of the patients on therapy. The high-resolution esophageal
manometry showed that end-expiratory LES pressures improved
and were sustained at 12-month follow-up [14].
In a post‑hoc analysis of patients that were incomplete respond-
ers to PPI therapy, Rodriguez et al. reported significant improve-
ment in outcomes of GERD–HRQL (9 vs 2; p < 0.01) and distal
esophageal pH (9.1 vs 3.5%; p < 0.01) [15]. In another post‑hoc
analysis of a subgroup of patients with abnormal proximal esopha-
geal acid exposure, a hallmark of proximal reflux, Crowell et al.
showed normalization of abnormal proximal esophageal acid
exposure in all patients (p = 0.01) [16]. The median (interquartile
range [IQR]) GERD–HRQL in these patients improved from 9
(6–10) on-PPI and 21 (20–24) off-PPI to 0 (0–3) at their 1-year
follow-up (p < 0.05) [16].
In an ongoing, prospective, open-label multicenter trial in symp-
tomatic GERD patients, Bredenoord et al. reported similar prelimi-
nary results with LES electrical stimulation [17]. The median (IQR)
GERD–HRQL scores at baseline off-PPI were 30 (24–37), which
improved to 6 (4–11) on LES electrical stimulation at 3 months
(p < 0.001), and 9 (7–13) at 6 months (p < 0.01). There was also a
significant improvement compared with the GERD–HRQL scores
on-PPI of 19 (8–22) at baseline. Patients’ median (IQR) esopha-
geal pH at baseline was 12.4% (8.8–15%) and improved to 3.6%
(2–10%; p = 0.07) at 3 months and 4.2% (2.7–6.7%; p = 0.01)
at 6 months. GERD–HRQL scores off-PPI improved by greater
than 50% in 92% (11 out of 12) of the patients that were able to
discontinue PPI use. Esophageal acid exposure either normalized or
improved by more than 50% in 83% (ten out of 12) of patients [17].
There have been no device or stimulation-related unanticipated
adverse events, or untoward sensation due to stimulation in any
of these studies. Swallowing function assessed by manometry
was shown to be unaffected and no dysphagia symptoms have
been reported.
These are encouraging results supporting the use of LES stim-
ulation for the treatment of GERD, but there are limitations.
The open-label design of these trials cannot control for placebo
or ‘regression to mean’ effects, which can be addressed by well
designed randomized controlled trials. However, improvement in
objective measures, such as esophageal pH sustained for 1 year,
suggests a true therapeutic effect. Patients with >3 cm hiatal her-
nia were excluded from the trial, which constituted of a significant
proportion of refractory GERD patients. Future trials should
evaluate patients with moderate 3–5 cm hiatal hernias that may
be treated by a combination of restoration of abdominal esopha-
gus, repair of the diaphragmatic hiatus and implant of the LES
stimulator. Finally, the generalizability of these results will be
established after the final results of a multicenter trial with a larger
number of patients are available.
In conclusion, early results suggest that the electrical stimula-
tion of the LES using a laparoscopically implanted LES stimu-
lation system is safe and effective in the treatment of GERD
and results in significant improvement of GERD symptoms of
heartburn and regurgitation, reduction in GERD medication use
and improvement in esophageal acid exposure and LES pressures
without causing adverse sensation or symptoms. The improvement
in patient outcomes is sustained over the long term. Furthermore,
LES electrical stimulation can be noninvasively optimized to indi-
vidual patient’s disease profile and changing needs over time to
achieve sustained improvement in patient outcomes.
Financial & competing interests disclosure
MD Crowell has been a consultant with EndoStim Inc. and the Chair of its
data monitoring committee. The author has no other relevant affiliations
or financial involvement with any organization or entity with a financial
interest in or financial conflict with the subject matter or materials discussed
in the manuscript. This includes employment, consultancies, honoraria,
stock ownership or options, expert testimony, grants or patents received or
pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
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gastroesophageal reflux disease patients.”
Crowell

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Implanted electrical devices & gastroesophageal reflux disease