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Original article Clinical endoscopy: Editorial| Volume 83, ISSUE 2, P334-336, February 2016

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Endoscopy of the “brain”: the next frontier in gastroenterology

      Abbreviations:

      ENS (enteric nervous system), IBS (irritable bowel syndrome), ICC (interstitial cells of Cajal)
      A frequently quoted line by W. Cumming about patients with what would come to be termed irritable bowel syndrome (IBS) goes like this: “The bowels are at one time constipated, at another lax, in the same person. How the disease has 2 such different symptoms I do not profess to explain.”
      Even though this sentiment was expressed nearly 2 centuries ago, most gastroenterologists will probably find it difficult to refute even today. However, even more ironic is the fact that our current approach to the diagnosis of IBS and other neurogastronterologic disorders is not very different from what was used in that era—which is to say, using symptoms both for diagnosis and as targets for treatment. Indeed, Cumming and his contemporaries would probably be surprised, and perhaps disappointed, that modern investigators have not been able to take advantage of the amazing advances in imaging pathology (at both the macrolevel and the microlevel) to shed light on this conundrum. Other specialties certainly seem to have done so; witness the rapid progress in hepatology since the popularization of the liver biopsy by Menghini in the late 1950s. Since then, liver biopsy with subsequent pathologic examination has become the standard of diagnosis in the field and has led to an understanding of the etiopathogenesis of multiple diseases that until then had been classified on the basis of symptoms and the color of urine. More importantly, such insight has taken us from diagnosis to cure for diseases like hepatitis B and C, all in 1 professional generation.
      By contrast, disorders of the enteric nervous system (ENS) and its connections (the so-called gut–brain axis) remain mired in symptom-based rather than pathophysiologic approaches. This is despite the fact that routine endoscopic procedures bring gastroenterologists within a few millimeters of the ENS, the “brain” in our guts and the second largest nervous system in the body, with hundreds of millions of neurons. The importance of “sampling” this nervous system has been illustrated in the example of gastroparesis, a prototypical disorder of the ENS. The Gastroparesis Clinical Research Consortium, funded by the National Institute of Diabetes and Digestive and Kidney Diseases, has now shown that with the use of surgically obtained full-thickness biopsy specimens, gastroparesis is associated with a phenotypic change in macrophages and associated cytokine release, along with a loss of interstitial cells of Cajal (ICC). Further, the loss of ICC correlates with impairment of gastric emptying, which is the defining hallmark of this disease.
      • Grover M.
      • Bernard C.E.
      • Pasricha P.J.
      • et al.
      Clinical-histological associations in gastroparesis: results from the Gastroparesis Clinical Research Consortium.
      This has raised for the first time the prospects of a real cure for this disorder and has been transformative on how we view motility and functional digestive disorders in general.
      We now need to expedite the translation and validation of this knowledge to other more prevalent disorders such as functional dyspepsia, IBS, and others. Clearly, this is not possible if we continue to rely on surgical techniques, which are clinically indicated only in patients with refractory disease who are undergoing invasive procedures such as placement of a feeding tube or electric stimulator in the case of gastroparesis. This is where the power of endoscopy can help with its attributes of (relative) noninvasiveness, safety, preservation of anatomy, and iterativeness. Endoscopic procedures have replaced or eliminated the need for more invasive surgical procedures in multiple disorders: variceal banding instead of portosystemic shunts, biliary stenting instead of choledochal jejunostomy, mucosal resection for local cancer instead of organ resection, to name a few. It should therefore be eminently feasible for endoscopists to quickly and safely obtain tissue samples from the gut wall that include the core elements of the ENS: neurons, glia, ICC, and any associated inflammatory cells.
      Indeed, such attempts have already begun, and good results have been demonstrated in animal studies and to a lesser extent in humans. Some of these approaches aim to mimic surgery; that is, obtaining full-thickness specimens and then cleverly sealing the defect.
      • Rajan E.
      • Gostout C.J.
      • Aimore Bonin E.
      • et al.
      Endoscopic full-thickness biopsy of the gastric wall with defect closure by using an endoscopic suturing device: survival porcine study.
      • Rajan E.
      • Gostout C.J.
      • Lurken M.S.
      • et al.
      Evaluation of endoscopic approaches for deep gastric-muscle-wall biopsies: what works?.
      • Rajan E.
      • Gostout C.J.
      • Lurken M.S.
      • et al.
      Endoscopic “no hole” full-thickness biopsy of the stomach to detect myenteric ganglia.
      This is probably the most comprehensive method, although it does carry a low risk of postbiopsy leakage, which may not be acceptable for conditions that may be considered relatively benign. A contrasting approach analyzes submucosal plexus neurons (which can be readily found in simple endoscopic biopsy specimens) as a surrogate measure for the rest of the enteric nervous system. This has been found to be potentially useful in patients with diabetes, who showed a significant reduction in neuronal counts,
      • Selim M.M.
      • Wendelschafer-Crabb G.
      • Redmon J.B.
      • et al.
      Gastric mucosal nerve density: a biomarker for diabetic autonomic neuropathy?.
      and in patients with functional dyspepsia.
      • Cirillo C.
      • Bessissow T.
      • Desmet A.S.
      • et al.
      Evidence for neuronal and structural changes in submucous ganglia of patients with functional dyspepsia.
      However, although this method offers the advantage of simplicity and safety, it may not capture other critical components of the ENS (such as ICC and smooth muscle), and it is not clear that the submucosal plexus will necessarily mirror a pathologic condition in the myenteric plexus, given the difference in their structure and function. Other investigators have begun exploring the utility of confocal probes, endocytoscopy, or both for the visualization of myenteric neurons using “third-space” techniques.
      • Ohya T.R.
      • Sumiyama K.
      • Takahashi-Fujigasaki J.
      • et al.
      In vivo histologic imaging of the muscularis propria and myenteric neurons with probe-based confocal laser endomicroscopy in porcine models (with videos).
      • Sumiyama K.
      • Tajiri H.
      • Kato F.
      • et al.
      Pilot study for in vivo cellular imaging of the muscularis propria and ex vivo molecular imaging of myenteric neurons (with video).
      • Pasricha P.J.
      Endoscopy 20 years into the future.
      However, the information obtained may be limited to obvious changes in morphology or neuronal counts. Although dye-based methods can significantly enhance these approaches in experimental models, their applicability to humans in vivo is unclear.
      • Schemann M.
      • Camilleri M.
      Functions and imaging of mast cell and neural axis of the gut.
      • Boesmans W.
      • Hao M.M.
      • Vanden Berghe P.
      Optical tools to investigate cellular activity in the intestinal wall.
      In the present study, Othman and colleagues
      • Othman M.O.
      • Davis B.
      • Soroseik I.
      • et al.
      EUS-guided FNA biopsy of the muscularis propria of the antrum in patients with gastroparesis is feasible and safe.
      present their results of yet another technique. These investigators used EUS to guide a 19-gauge needle into the deep muscle layer of the gastric antrum in patients with diabetic gastroparesis undergoing neurostimulator placement. Aspiration of tissue from this site yielded enough material to stain for ICC in about 80% of patients and neuronal bundles in about half. Cell counts were then compared with those from surgically obtained full-thickness biopsy specimens with a “good” correlation coefficient.
      However, whether or not this technique will eventually prove to be of clinical value remains to be seen. First, the study likely overestimated the number of ICC by counting portions of ICC processes instead of restricting the count to ICC bodies, which is the current standard. Indeed, a quick “back of the envelope” calculation shows that there may be no statistically significant correlation between ICC counts from tissue obtained by EUS-FNA and those obtained by surgery. This is not surprising, for a variety of other reasons. Absence of field sizes used for quantification and the lack of a nonblinded pathologist make it difficult to draw comparisons between the EUS-guided and surgical approaches. Another issue is related to the technique itself: by its nature, fragmented tissue does not allow sophisticated analysis requiring proper tissue orientation for defining cellular changes in different layers of the muscularis propria (circular muscle, myenteric plexus, and longitudinal muscle). There are also significant issues with neuronal counting in this study. The investigators describe nerve bundles, leaving it unclear as to how often nerve cell bodies were present. Further, the staining used (S100) also stains glia, thus lessening confidence in the accuracy of neuronal counts.
      Nevertheless, these investigators are to be congratulated on their creativity and their desire to push the envelope in terms of facilitating a pathologic diagnosis of gastroparesis. Their study also highlights the significant hurdles that need to be overcome before this and other endoscopic techniques can become mainstream.
      To begin with, accurate diagnosis requires normative standards. Unfortunately, these do not generally exist. The ENS is an enormously complex system with multiple cell types and subtypes (including a dozen or more neuronal phenotypes); furthermore, its composition may vary both within the different organs and in different regions of the same organ. However, this kind of “mapping” has not been done even on surgical or autopsy specimens and is a major prerequisite for advancement of the field regardless of the technique for tissue acquisition. The problem is further compounded by the likely possibility that techniques involving needle aspiration need to be highly standardized to be reproducible and may require norms of their own, unique from those obtained by full-thickness biopsy. Finally, it is possible that some disorders are patchy in nature, and random sampling of tissue may miss underlying pathologic conditions.
      Despite these caveats, there is no question that the field of neurogastroenterology will benefit tremendously from safe and simple access to the ENS. This has the potential for being transformative in so many ways—positive diagnoses rather than diagnoses based on symptoms and exclusion of other disorders, clues to pathogenesis, and ultimately curative therapies. Thus, we encourage endoscopic researchers to pursue these activities in a rigorous fashion and give us true insight into the mysteries of the second “brain.”

      Disclosure

      All authors disclosed no financial relationships relevant to this publication.

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      Linked Article

      • EUS-guided FNA biopsy of the muscularis propria of the antrum in patients with gastroparesis is feasible and safe
        Gastrointestinal EndoscopyVol. 83Issue 2
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          EUS-guided FNA biopsies of the muscularis propria of the gastric wall in patients with gastroparesis could replace the routine use of surgical full-thickness biopsies for assessing the loss of the interstitial cells of Cajal (ICCs) and cellular infiltrates in the myenteric plexus. We investigated the efficacy and safety of EUS-guided FNA biopsies of the muscularis propria of the gastric antrum in gastroparesis and compared the tissue with a surgically obtained full-thickness biopsy specimen in the same patient.
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