Introduction
Innovations in the field of gastrointestinal (GI) endoscopy over the last two decades
have made it possible to reach the earlier inaccessible areas in the GI tract. Methods
of deep small bowel endoscopy by balloon-assisted enteroscopy were far from ideal
due to sub-optimal pan-enteroscopy rates and prolonged procedure time. Difficult biliary/pancreatic
stones and indeterminate strictures were often subjected to surgical therapy. GI diseases
such as achalasia cardia and refractory gastroparesis often required surgical myotomy
until submucosal space was recognized as a potential operative field as third-space
endoscopy evolved. All these potential barriers in interventional endoscopy have been
circumvented by newer technologies such as motorized spiral enteroscopy, cholangiopancreatoscopy,
and third-space endoscopy. These innovations are propelling the field of advanced
GI endoscopy forward. We describe our experience with regard to the technological
evolutions and landmarks we observed over the last two decades.
Venturing Deep into Small Bowel
Evolution of Small Bowel Enteroscopy
The first breakthrough in deep enteroscopy began with the invention of the double-balloon
enteroscope (DBE) (Fujifilm, Tokyo, Japan) way back in 2001 in Japan by Hironori Yamamoto.[1] This was followed by the introduction of single-balloon enteroscopy (SBE) (Olympus
Medical Systems Corp, Tokyo) in 2007.[2] Compared with DBE, SBE has only one balloon located at the tip of the over-tube
and uses the hooked tip of the endoscope to fix the intestine. SBE is non-inferior
to DBE with regard to the depth of insertion, diagnostic yield, and rate of complications
with shorter preparation and investigation time although panenteroscopy rates are
better with DBE.[3] Principles of balloon-assisted enteroscopy (BAE) depend upon the serial “push and
pull maneuver” to pleat the small intestine. A large study from India including 106
patients showed diagnostic yields of 55%, 60%, and 65% for chronic diarrhea, obscure
GI bleed, and chronic abdominal pain, respectively, with a 25% panenteroscopy rate.
Therapeutic interventions were performed in 21% via SBE, which included argon plasma
coagulation (APC), polypectomy, stricture dilatation, foreign body extraction, and
hemoclips for jejunal Dieulafoy's lesion ([Fig. 1]).[4]
Fig. 1 “Breaking the barrier in endoscopy”: evolution of deep enteroscopy, chonagiopancreatoscopy,
and third-space endoscopy (peroral endoscopic myotomy: POEM); POEM-F: peroral endoscopic
myotomy with fundoplication.
After SBE, manual spiral enteroscopy (SE) (Spirus Medical, Stoughton, Mass, USA) was
introduced in 2008.[5] SE depends on the principle of “rotation” rather than “push and pull.” The spiral
overtube was 118 cm long, which was compatible with standard single and double-balloon
enteroscope (200 cm). This left only 90 to 95 cm of effective length and only 30 to
35 cm of functional scope beyond the ligament of Treitz to perform small bowel pleating,
making it difficult to perform pan-enteroscopy even by the most experienced endoscopist.
Also, the requirement for manual spiral rotation caused significant wear and tear
on the endoscopist. SE has a similar diagnostic and therapeutic yield, similar depth
of insertion but importantly shorter procedure time compared with BAE based on a systematic
review and meta-analysis.[6] In a series of 11 cases of SE reported from India, the mean procedure time was 27.8 minutes
(range: 20–32 minutes) (considerably lower than BAE) with an average depth of insertion
of 249 cm (120–400 cm). No major complications were noted.[7]
Novel Motorized Spiral Enteroscopy
NMSE has addressed prior technical challenges in SE. It uses a longer enteroscope
(working length 168 cm) with a short spiral over-tube (24 cm), which increases the
likelihood of pan-enteroscopy. An integrated water jet system and a larger working
channel diameter (3.2 mm) allow for better therapeutic endoscopy.[8] A user-controlled spiral motor unit allows for a single operator to perform the
procedure in an even faster and simplified manner. In a prospective clinical feasibility
study of 140 procedures performed in two centers; the technical success, diagnostic
yield, median depth of insertion, median insertion time, anterograde pan-enteroscopy
rate, and major adverse events were 97%, 74.2%, 450 cm, 25 minutes, 10.6% and 1.5%
respectively.[9] Total enteroscopy rate was reported to be 70% (in 53.4% pan-enteroscopy was achieved
by bidirectional approach and in 16.6% cases by only antegrade approach).[10] Compared with western studies, the first real-world data from India on diagnostic
yield and therapeutic impact of NMSE showed pan-enteroscopy rate was 60.6% of which
31.1% was noted in antegrade and 29.5% in bidirectional enteroscopy. Technical success
and diagnostic yields were 93.4% and 65.5%, respectively. Also, 23% of patients underwent
therapeutic spiral enteroscopy. No serious adverse events were reported. The major
advantages of NMSE are shorter procedure time, single-operator use, higher pan-enteroscopy
rates, and better provision of therapeutic small bowel endoscopy.[8] NMSE-guided removal of the impacted video capsule endoscope in distal ileum in a
case of multifocal stricturizing Crohn's disease after balloon dilation of strictures
has been reported.[11] This has the potential to revolutionize the management of small bowel disorders
([Fig. 2]).
Fig. 2 Novel motorized spiral enteroscopy (NMSE). (A) Antegrade pan-enteroscopy with NMSE: contrast injection showing opacification of
the cecum, (B) Retrograde pan-enteroscopy with NMSE: contrast injection showing opacification of
duodenal bulb, (C) Circumferential non-passable ulcerated stricture in mid ileum seen via antegrade
route.
Exploring the Ducts
Evolution of Cholangioscopy and Pancreatoscopy
Endoscopic retrograde cholangiopancreatography (ERCP) is the main diagnostic and therapeutic
modality for biliary tract disorders that use fluoroscopy. However, ERCP has limitations
in various biliary tract disorders such as stricture, tumor, cyst, and filling defects
that may warrant direct visualization of the biliary tract. Differentiating benign
and malignant biliary disease with brush cytology and biliary biopsy is suboptimal.
Also, 5 to 10% of biliary stones may not be amenable to ERCP, endoscopic papillary
balloon dilation (EPBD), and even mechanical lithotripsy.[12] To overcome the limitations, per-oral cholangioscopy was first performed in 1975.
Since then, there are serial advancements in methods, accessories, and techniques
the last few decades ([Fig. 1]).
Cholangioscopy can be done peroperatively, per-orally, or through percutaneous trans-hepatic
route. The percutaneous route requires a large diameter, trans-hepatic tract that
requires time to mature and is associated with risk of bile leak, bleeding, and tumor
seeding along the tract. Hence, per-oral cholangioscopy is most popular that can be
done directly via ultra-thin caliber endoscope or indirectly via the insertion of
a cholangioscope through the accessory channel of the duodenoscope. Direct peroral
cholangioscopy (DPOC) requires prior sphincterotomy/sphincteroplasty for the advancement
of ultra-thin caliber endoscope. It is technically challenging due to the looping
of the endoscope in the stomach and the lack of stability while advancing the endoscope
through the biliary system. Hybrid balloon catheter anchoring device and double bending
cholangioscope are the few of those technical modifications to overcome the challenges.
Moreover, the risk of air embolism is present that may occur due to excessive gas
pressure in thin caliber biliary system.[12] Advantages of DPOC include higher image resolution and higher caliber of the accessory
channel. Image-enhanced endoscopy (IEE) during DSOC can help differentiate benign
from a malignant tumor and define tumor margin by evaluating surface and micro-vasculature.
Indirect cholangioscopy using mother duodenoscope and baby cholangioscope requires
two operators, has highly fragile instruments, and is associated with high cost. It
has fallen out of favor due to the above factors along with poor image resolution,
provision of only two way deflection of cholangioscope tip, longer set up, and procedure
time.[12]
Single Operator Peroral Cholangioscopy
Single operator system initially consisting of the directable plastic sheath and a
reusable fiber-optical light and image guide (Legacy SpyGlass, Boston Scientific,
Marlborough, Massachusetts) have addressed some of the limitations of a dual operator
system. It can be advanced into the biliary system with or without wire guidance by
a single operator controlling the mother duodenoscope and 3.3 mm diameter baby cholangioscope.
Cholangioscope has a four-way tip deflection and two channels (for irrigation and
suction). This allows for higher maneuverability and passage of accessories such as
biopsy forceps, endomicroscopy probe, snare, or basket allowing therapeutic procedures
such as laser or electrohydraulic lithotripsy (EHL).[12] A prospective study from India has demonstrated that the visual impression of the
SpyGlass is accurate in 89% of cases to differentiate benign from the malignant lesion,
whereas targeted SpyBite biopsies are accurate in 82%, which is far higher than brushing
cytology/blind biliary biopsy. Irregularly dilated tortuous vessels, papillary/villous
projections, and nodularity/mass were the characteristics of a malignant lesion. A
homogenous granular mucosa devoid of any mass and smooth surface without neovascularization
were criteria for benign lesions.[13] In a series of five cases from India showed that SOPOC with intraductal ultrasound
(IDUS) can be helpful in the evaluation and management of portal biliopathy when the
cause of obstruction is not well defined by identifying pericholedochal collaterals,
intraductal varices or ischemic stricture.[14]
Digital Single Operator Cholangioscopy
Cholangioscopy was revolutionized using DSOC (SpyGlass DS, Boston Scientific) with
disposable cholangioscope that captures images digitally. DSOC is superior to fiberoptic
single operator cholangioscopy (FSOC) with regard to image quality, visualization
and maneuverability, especially for targeting left intraductal lesion in a randomized
novel cholangioscopy bench model study ([Fig. 3]).[15]
Fig. 3 SpyGlass DS single operator cholangioscopy. (A) Benign stricture on cholangioscopy showing smooth surface without neovascularization.
(B) IgG4 related cholangiopathy-related stricture on cholangioscopy. (C) Nodularity and irregular vessels in a tight malignant stricture negotiated with
catheter. (D) Spybite biopsy being taken during cholangioscopy. (E) Impacted stone is seen on cholangioscopy. (F) Stone fragmentation by laser lithotripsy.
The advantages of DSOC include:
-
(1) Feasibility of radiation-free ERCP
-
(2) Direct visualization of the biliary system
-
(3) Tissue acquisition
-
(4) Cholangioscopy-directed therapy
Radiation-free ERCP could be valuable particularly in pregnant females as shown in
a recent multicenter study, in which DSOC helped in avoiding fluoroscopy in 50% of
cases.[16]
A multi-center randomized controlled study has shown higher sensitivity (68.2%) and
accuracy (76.7%) of DSOC-guided tissue sampling compared with conventional ERCP-guided
brush cytology (21.4% sensitivity, 59.3% accuracy) with similar adverse event profile
in indeterminate biliary strictures.[17] Importantly, the visual impression on DSOC had a sensitivity of 95.5% with an overall
accuracy of 87.1%.[17] This has important clinical implications as malignant-looking operable lesions on
cholangioscopy can be offered surgery even if tissue sampling is inconclusive. An
expert consensus statement has enumerated indications of peroral cholangiography:
(1) targeted biopsy in indeterminate biliary strictures, (2) cholangioscopy-guided
lithotripsy when standard techniques fail.[18] This has been substantiated by two recent large multi-center studies. The first
one on cholangioscopy-guided tissue acquisition showed that cholangioscopic visual
impression and tissue acquisition had an overall accuracy of 77.2% and 86.5%, respectively.[19] The second one showed that cholangioscopy-guided lithotripsy was effective in stone
clearance in a single session in 80% of cases (among whom 80% had earlier failed ERCP),
especially for less than 3 cm stones.[20] Latest consensus guidelines state that cholangioscopy-guided visualization and -guided
biopsy during initial ERCP may reduce the need for multiple procedures in indeterminate
strictures (except for distal biliary strictures) although it is associated with a
higher risk of cholangitis than standard ERCP necessitating prophylactic antibiotics
and adequate biliary drainage.[21]
Single Operator Pancreatoscopy
Single operator pancreatoscopy (SOP) has been used for the evaluation of indeterminate
pancreatic duct strictures and intraductal papillary mucinous neoplasm (IPMN). Therapeutic
interventions such as intraductal lithotripsy and even intraductal necrosectomy in
walled-off necrosis (WON) have been described.[22] In a large single-center study (n = 41), SOP helped in directed biopsy and classification in suspected IPMN and impacted
clinical management in 76% by providing additional information or tissue diagnosis.
Post ERCP pancreatitis occurred in 17%.[23]
SOP-guided electrohydraulic lithotripsy (EHL) and laser lithotripsy (LL) can achieve
complete ductal clearance in 89.9% and a single session was required in 73.5% according
to a large (n = 109) retrospective analysis. More than three stones were independent predictors
of multiple sessions.[24] In a retrospective cohort study comparing SOP-guided lithotripsy versus extracorporeal
shock wave lithotripsy (ESWL), SOP-guided lithotripsy was associated with the requirement
of less number of sessions and more complete clearance with similar adverse event
rates. Stones > 1 cm was associated with failure of SOP-guided lithotripsy.[25]
Step Out of Gut Wall
Evolution of Third-Space Endoscopy
The scope of therapeutic endoscopy has increased manyfold with the introduction of
natural orifice trans-luminal endoscopic surgery (NOTES). This has enabled the entry
of flexible endoscopy into the second- and third-space (peritoneal cavity and submucosal
space respectively). One of the major concerns with third space endoscopy was secure
closure of the mucosal defect. Sumiyama et al have shown the safety of submucosal
endoscopy with mucosal flap safety valve (SEMF) in which entry into the peritoneal
cavity was safely closed with mucosal flap.[26] Using the SEMF technique, Pasricha et al first performed endoscopic myotomy in an
animal model in 2007.[27] Subsequently, Inoue performed the first human case of peroral endoscopic myotomy
(POEM) in 2008.[28] The first case of submucosal tunneling and endoscopic resection (STER) for the submucosal
tumor was also performed by Inoue in 2012.[29] Now, third-space endoscopy with SEMF is used in various GI disorders such as achalasia
(POEM), sub-epithelial tumor (STER/peroral endoscopic tunneling: POET), refractory
gastroparesis (gastric or G POEM), Zenker's diverticulum (Z-POEM), and esophageal
stricture (POETRE-peroral endoscopic tunneling for restoration of the esophagus).[26] Among these, POEM is the most popular technique of third-space endoscopy with vast
experience worldwide. Gastroesophageal reflux disease (GERD) is the Achilles' heel
of POEM procedure as a treatment of achalasia. New novel modalities such as POEM with
endoscopic fundoplication have been introduced to mitigate this issue which was first
reported by Inoue et al.[30]
Peroral Endoscopic Myotomy
Peroral endoscopic myotomy (POEM) is the most extensively studied third-space endoscopic
procedure. The steps are submucosal injection, mucosal incision, submucosal tunneling,
myotomy, and mucosal incision closure ([Fig. 4]). Studies have shown excellent short and midterm results of POEM for achalasia but
long-term results are scarce.[26] Also, 94% clinical success rate at 1 year has been reported in a prospective study
of 200 achalasia patients undergoing POEM.[31] Subsequently the mid-term follow-up data (3 years) of 408 patients showed the highest
clinical success at 3 years for type II achalasia (93.5%) followed by type I (87.5%)
and type III achalasia (75%).[32] Similar efficacy and safety of POEM for prior treatment failure cases compared with
treatment-naive patients have been shown in an analysis of more than 500 patients.[33] Various technical issues such as anterior versus posterior myotomy and short (3 cm)
versus long myotomy (≥ 6 cm) have also been addressed by studies from India in randomized
controlled trials. Anterior and posterior POEM had similar treatment efficacy where
mucosectomies were more common in anterior POEM, whereas GERD was more common in posterior
myotomy due to disruption of sling fibers.[34] Short myotomy was shown to have similar success rates, adverse events, and GERD
in type I and II achalasia with significantly shorter operating times.[35] Type III achalasia requires long myotomy. Most of the adverse events are insufflation-related
(e.g., pneumoperitoneum) that do not require active intervention and can be managed
during the procedure without untoward consequences.[31] Early recognition of bleeding points and hemostasis can be done by red dichromatic
imaging (RDI).[36] A novel multipurpose bipolar device can help obviate the need for a change of accessories
in third space endoscopy as shown in a series of 10 cases which included seven cases
of achalasia.[37] POEM was also shown to be an effective and durable treatment for spastic esophageal
motility disorders (Type III achalasia, Jackhammer esophagus, distal esophageal spasm-
DES) with long term (5 years) success rate of 82.6%.[38]
Fig. 4 Third-space endoscopy A–D: steps of POEM. (A) Mucosal incision. (B) Submucosal tunneling. (C) Myotomy. (D) Mucosal incision closure. (E–H) Endoscopic submucosal dissection (ESD). (E) Laterally spreading rectal tumor seen on a narrow band imaging near focus. (F) Mucosal incision. (G) Submucosal dissection. (H) Tumor bed after complete resection: turned out to be high-grade dysplasia.
Most cases of post POEM GERD have been shown to be mild and proton pump inhibitor
(PPI) responsive. None of the procedure-related factors can predict post POEM GERD.[39] Identifying the twin penetrating vessels during myotomy can help prevent disruption
of oblique fibers and thus GERD.[40] Other novel technique to reduce reflux was simultaneous endoscopic fundoplication
(POEM-F).[41] Post POEM heartburn can occur due to acid fermentation, delayed esophageal clearance,
stasis, and esophageal hypersensitivity other than true acidic reflux.[42]
Third Space Endoscopy beyond POEM
Large (>3 cm), submucosal tumors arising from muscularis propria can have malignant
potential and can be resected endoscopically by submucosal tunneling and endoscopic
resection (STER). The steps are similar to POEM except for tumor dissection and en
bloc removal by snare instead of the myotomy.[26] In a large series of 44 patients from India reported 99.7% technical success and
88.4% en bloc tumor removal with STER. Minor adverse events occurred in 16.9% without
any major adverse events. Leiomyoma and gastrointestinal stromal tumors (GIST) are
the most common submucosal tumors resected. There was no difference in recurrence
rate among those with piecemeal or en-bloc resection ([Fig. 4]).[43]
Gastric POEM with pyloromyotomy can be helpful in refractory gastroparesis when pylorospam
is the main pathophysiologic mechanism. It has comparable efficacy as laparoscopic
pyloromyotomy with lower postoperative morbidity according to a prospective matched
control study.[44]
Z -POEM for Zenker's diverticulum can reduce the risk of perforation compared with
conventional myotomy as the mucosa is preserved in D-POEM.[26] Division of epiphrenic diverticulum (D-POEM) has been described by a single-center
study from India in 13 patients with three quarters having associated motility disorder.
It was effective in all cases with a single report of the major adverse event warranting
surgery.[45]
