Endoscopy is an essential tool for effective care of patients with inflammatory bowel disease (IBD), including Crohn disease and ulcerative colitis. The newest endoscopic small-field imaging technologies with confocal endomicroscopy have allowed real-time imaging of gastrointestinal mucosal during ongoing endoscopic evaluation and in vivo histology. Thus, endomicroscopy has a potential to further enhance the endoscopic evaluation of IBD. Advances in molecular in vivo imaging in IBD may be used not only to better understand the pathophysiology of IBD but also to guide optimized therapy and thus to allow a personalized, new approach to the IBD management.
Key points
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Confocal laser endomicroscopy (CLE) is a rapidly emerging tool in endoscopic imaging allowing in vivo microscopy of examined gastrointestinal mucosa. CLE also has the potential to enhance the endoscopic evaluation of inflammatory bowel disease (IBD). This may be achieved by further characterization of otherwise normal-appearing mucosa, assessment of the barrier function of the epithelium, and characterization of any mucosal lesions including dysplastic lesions.
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Imaging of intestinal inflammation in IBD by CLE may be of special importance not just for the diagnosis of IBD, assessment of severity of inflammation but also for predicting severity and the guidance of therapy. This would represent a true advantage of CLE over the conventional white-light endoscopy in evaluation of IBD and assessment of a true mucosal healing.
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Advances in IBD may be used not only to better understand the pathophysiology of IBD but also to guide optimized therapy and thus allow a completely new, personalized approach to the IBD management.
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Further studies are needed to fully evaluate and validate the promising results of CLE studies in IBD.
Introduction
Endoscopy is an essential tool in effective evaluation of patients with inflammatory bowel disease (IBD). The endoscopic evaluation of IBD includes not only diagnosing the disease, assessing the disease’s extent and activity, but also treating its complications, monitoring the responses to treatment with evaluating mucosal healing, and serving as a predictor of disease course. The small-field endoscopic imaging technology, such as confocal laser endomicroscopy (CLE) has allowed real-time imaging of gastrointestinal mucosal during ongoing endoscopic evaluation in various gastrointestinal pathologies. It also has the potential to enhance endoscopic evaluation in IBD. CLE is based on tissue illumination with a low-power laser allowing micron-level spatial resolution with ×1000 magnification. To obtain images, exogenous fluorescence contrast is applied with agents such as fluorescein (10% 5 mL solution, intravenous application), or acriflavine hydrochloride or cresyl violet (topical applications). Intravenous fluorescein (1.0–5.0 mL of 10% solution) distributes throughout the capillary network and connective matrix and has been universally applied in all confocal studies and is found to be generally safe in use. Until recently, CLE has been performed using 1 of 2 Food and Drug Administration (FDA)-approved devices: endoscope-based confocal laser endomicroscopy (Pentax, Fort Wayne, NJ; herein termed eCLE) and a stand-alone probe CLE (herein termed pCLE) capable of passage through the accessory channel of most endoscopes (Cellvizio, Mauna Kea Technologies, Paris, France). Currently the eCLE system is no longer clinically available, although most clinical applications have been studied based on that system.
The probe-based CLE system (pCLE), introduced in 2005, consists of a stand-alone confocal probe, capable of passage through an accessory channel of most endoscopes. The probe is made of 30,000 optical fibers bundled together with a distal lens and a proximal precision connector. The proximal connector attaches the probe to the laser scanning unit that is connected to a standard computer for image data processing and display ( Fig. 1 ). Table 1 lists the features of the 2 CLE systems: the current probe based and the prior endoscope based.
| System | Current System: Probe-Based CLE (pCLE) (Cellvizio, Mauna Kea Technologies, Paris, France) | Prior System: Endoscope-Based CLE (eCLE) (Pentax, Japan) |
|---|---|---|
| Magnification | 1000 times | 1000 times |
| Lateral Resolution | >1 μm | <1 μm |
| Field of view | 240–600 μm | 475 × 475 μm |
| Imaging plane depth | 40–130 μm (fixed) | 0–250 μm (variable) |
The value of CLE in evaluation of conditions such as Barrett esophagus, colorectal polyps, and celiac disease has been demonstrated and validated in various studies. CLE also has the potential to enhance the endoscopic evaluation of IBD. This may be achieved by further characterization of the barrier function of the epithelium, assessment of inflammatory activity, characterization of any mucosal lesions, and ultimately predicting severity, disease extent, and response to the treatment. Imaging of intestinal inflammation in IBD by CLE may be of special importance not just for the diagnosis of IBD but also for the guidance of therapy. Furthermore, advances in molecular in vivo imaging in IBD may be used to better understand the pathophysiology of IBD and to guide an optimized therapy. This review discusses the most recent advances and potential applications of confocal endomicroscopy and molecular tools in the evaluation of IBD.
Introduction
Endoscopy is an essential tool in effective evaluation of patients with inflammatory bowel disease (IBD). The endoscopic evaluation of IBD includes not only diagnosing the disease, assessing the disease’s extent and activity, but also treating its complications, monitoring the responses to treatment with evaluating mucosal healing, and serving as a predictor of disease course. The small-field endoscopic imaging technology, such as confocal laser endomicroscopy (CLE) has allowed real-time imaging of gastrointestinal mucosal during ongoing endoscopic evaluation in various gastrointestinal pathologies. It also has the potential to enhance endoscopic evaluation in IBD. CLE is based on tissue illumination with a low-power laser allowing micron-level spatial resolution with ×1000 magnification. To obtain images, exogenous fluorescence contrast is applied with agents such as fluorescein (10% 5 mL solution, intravenous application), or acriflavine hydrochloride or cresyl violet (topical applications). Intravenous fluorescein (1.0–5.0 mL of 10% solution) distributes throughout the capillary network and connective matrix and has been universally applied in all confocal studies and is found to be generally safe in use. Until recently, CLE has been performed using 1 of 2 Food and Drug Administration (FDA)-approved devices: endoscope-based confocal laser endomicroscopy (Pentax, Fort Wayne, NJ; herein termed eCLE) and a stand-alone probe CLE (herein termed pCLE) capable of passage through the accessory channel of most endoscopes (Cellvizio, Mauna Kea Technologies, Paris, France). Currently the eCLE system is no longer clinically available, although most clinical applications have been studied based on that system.
The probe-based CLE system (pCLE), introduced in 2005, consists of a stand-alone confocal probe, capable of passage through an accessory channel of most endoscopes. The probe is made of 30,000 optical fibers bundled together with a distal lens and a proximal precision connector. The proximal connector attaches the probe to the laser scanning unit that is connected to a standard computer for image data processing and display ( Fig. 1 ). Table 1 lists the features of the 2 CLE systems: the current probe based and the prior endoscope based.
| System | Current System: Probe-Based CLE (pCLE) (Cellvizio, Mauna Kea Technologies, Paris, France) | Prior System: Endoscope-Based CLE (eCLE) (Pentax, Japan) |
|---|---|---|
| Magnification | 1000 times | 1000 times |
| Lateral Resolution | >1 μm | <1 μm |
| Field of view | 240–600 μm | 475 × 475 μm |
| Imaging plane depth | 40–130 μm (fixed) | 0–250 μm (variable) |
The value of CLE in evaluation of conditions such as Barrett esophagus, colorectal polyps, and celiac disease has been demonstrated and validated in various studies. CLE also has the potential to enhance the endoscopic evaluation of IBD. This may be achieved by further characterization of the barrier function of the epithelium, assessment of inflammatory activity, characterization of any mucosal lesions, and ultimately predicting severity, disease extent, and response to the treatment. Imaging of intestinal inflammation in IBD by CLE may be of special importance not just for the diagnosis of IBD but also for the guidance of therapy. Furthermore, advances in molecular in vivo imaging in IBD may be used to better understand the pathophysiology of IBD and to guide an optimized therapy. This review discusses the most recent advances and potential applications of confocal endomicroscopy and molecular tools in the evaluation of IBD.
Confocal laser endomicroscopy for assessment of inflammation, barrier function of epithelium, and disease relapse
As the field of IBD therapy has moved to a “treat-to-target” approach, with the goal of suppressing microscopic inflammation, CLE may play an important role in assessing disease activity with detection of all inflammatory features, assessing the degree of inflammation as well as evaluating the barrier function of the epithelium. CLE may also facilitate the distinction between ulcerative colitis (UC) and Crohn’s disease (CD).
Assessment of Inflammation and Mucosal Healing
As compared with healthy mucosa, inflamed mucosa in IBD on CLE examination has been noted for irregular and tortuous crypt with irregular and wider lumens. In addition, an increased density of epithelial gaps and fluorescein leakage to the interstitial space also has been detected by CLE in IBD. This is in contrast to noninflamed mucosa in which epithelium functions as an intact barrier not allowing fluorescein leakage and crypts are round and regular with small round lumina. CLE may identify IBD-associated histologic changes in macroscopically noninflamed mucosa. The new classification of pCLE in IBD to predict histologic inflammation in noninflamed-appearing mucosa based on different vessel and crypt categories was developed and validated by Neumann and colleagues with an overall acceptable accuracy of 87%.
Endoscopic assessment of mucosal healing in IBD has been recognized as an important measure of disease activity, therapeutic goal, and prognostic factor. Mace and colleagues, in their recent control study of 12 patients with UC in remission (UC-IR), aimed to determine whether endoscopically normal mucosa can be also confirmed by CLE to have fully resolved inflammation. Although in control patients CLE demonstrated normal colon crypts and microvessels, colonic mucosa of patients with UC-IR was noted to have impaired crypt regeneration, persistent inflammation, and increased vascular permeability. Thus, CLE imaging may allow a more adequate assessment of mucosal healing in IBD. Further studies are needed to validate these initial observations. Furthermore, CLE may help to differentiate between UC and CD. In the recent study by Tontini and colleagues, a new CLE-IBD differentiation score based on endomicroscopy assessment (IDEA) has been introduced evaluating parameters such as presence or absence of architecture distortion, irregular surface, decreased crypt density, discontinuous crypt architectural abnormality, focal cryptitis, and discontinuous inflammation. The IDEA score was shown to have excellent accuracy of 93.7% when compared with the historical clinical diagnosis and the histopathological gold standard diagnosis. CLE was able to visualize several disease-specific microscopic features used in standard histopathology, although due to limited penetration depth of CLE, subtle submucosal details and granulomas could not be evaluated.
Assessment of Degree of Inflammation and Disease Activity
The correlation between CLE features of the crypts and the inflammation assessed by regular histopathology has been specifically examined in recent studies in patients with UC and patients with CD. The Chang–Quing scale has been introduced assessing the degree of inflammation based on the crypt architecture: the regularity of crypt arrangement, crypt density, dilation of crypt lumens, and crypt destruction and subsequently validated by comparison with endoscopic assessment and clinical outcomes in UC. Li and colleagues demonstrated good correlation between CLE assessment of crypt architecture and fluorescein leakage with histologic results in patients with UC. Interestingly, more than half of the patients with normal mucosa seen on conventional white-light endoscopy showed acute inflammation on histology, whereas no patients with normal mucosa or with chronic inflammation seen on CLE showed acute inflammation on histology. Assessment of microvascular alteration by CLE also showed good correlation with histologic finings. The presence of fluorescein leakage correlated with histologic assessment of inflammation. The additional studies in UC compared the CLE-documented inflammation with histopathology assessment. Based on those studies, the CLE assessment of crypts’ architecture strongly correlated with the degree of inflammation assessed by histology, while higher level of fluorescein leakage was noted in active disease as compared with quiescent disease. Buda and colleagues divided patients with UC into 3 groups depending on a composite outcome score combining the amount of fluorescein leakage and crypt diameters and determined that this composite outcome score was able to predict a disease flare during a 12-month follow-up period ( P < .01). Specifically depending on each group’s score, relapse rate ranged from 6 of 7, 1 of 6, and 0 of 6 during the following year.
Based on those studies, the crypt architecture, microvascular alteration, and fluorescein leakage can represent promising markers in CLE evaluation of IBD, although further studies validating these initial observations are required.
Neumann and colleagues evaluated CLE features of inflamed mucosa in patients with CD. The Crohn’s Disease Endomicroscopic Activity Score (CDEAS) to evaluate CD colitis activity in vivo (active vs nonactive) was developed in a prospective study of 54 patients with CD using eCLE and pCLE. The CDEAS included parameters such as crypt number (increased, decreased), colonic crypt distortion microerosions, augmented vascularization, number of goblet cells (increased or decreased), and increased cellular infiltration within lamina propria. By assigning 1 point for each given parameter, the total score ranged from 0 to 8. Quiescent CD colitis was noted to have a significant increase in crypt and goblet cell numbers with median CDEAS score of 2, whereas patients with active colitis had a score of 5. There was also significant association of the CDEAS score with inflammatory markers, such as C-reactive protein, but further associations with histology, endoscopic assessment, and clinical outcomes are to be established.
In addition, the Watson grading system has been introduced and based on parameters such as fluorescein leakage to the lumen of the small intestine and the presence of microerosions. The system has been also compared with the clinical outcomes but not endoscopic or histologic assessment of IBD. Table 2 compares all available the CLE-based systems for the inflammation assessment in IBD.
Related posts:
The First Endoscopy in Suspected Inflammatory Bowel Disease
Capsule Endoscopy and Deep Enteroscopy in Inflammatory Bowel Disease
Role of Histologic Inflammation in the Natural History of Ulcerative Colitis
The Gastroenterologist’s Role in Management of Perianal Fistula
Motility Evaluation in the Patient with Inflammatory Bowel Disease
Dilation of Strictures in Patients with Inflammatory Bowel Disease
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