Confocal Microscopy

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Article initiated by:
Elmira Baghdasaryan, MD
All contributors:
Brad H. Feldman, M.D., Vatinee Y. Bunya, MD, MSCE, Maria A. Woodward, MD, Elmira Baghdasaryan, MD, Sumayya Ahmad, MD, Sezen Karakus, MD
Assigned editor:
Sumayya Ahmad, MD
Review:
Assigned status Update Pending
 by Sumayya Ahmad, MD on March 21, 2024.


Description/Overview

In vivo confocal microscopy (IVCM) is an emerging noninvasive imaging and diagnostic tool, which enables morphological and quantitative analysis of ocular surface microstructure. The principal of confocal microscopy was patented in 1957 by Marvin Minsky .[1]The key elements of Minsky's confocal microscope design included the pinhole apertures, point-by- point illumination of the specimen and rejection of out-of-focus light.[2] Tandem-scanning microscopes were the first commercialized confocal microscopes introduced in the 1960s in Czechoslovakia. In 1969, the first laser scanning confocal microscopes were developed at Yale University.[3]

The most used IVCM used today in clinical practice and reported in the published literature are Confoscan Series (Nidek Co. Ltd., Gamagori, Japan) and the Heidelberg Retina Tomograph II (HRT-II)/Rostock Cornea Module (RCM) (Heidelberg Engineering GmbH, Heidelberg,Germany). The Confoscan 4 confocal microscope uses a slit scanning design. The slit scanning microscope has the advantage of scanning many points in parallel, but the disadvantage is that this microscope is truly confocal only in the axis perpendicular to the slit. [4] Confoscan 4 has 20× lens that works 12 mm from the corneal apex for endothelial cell count, allowing a fully no-contact exam. Its z-adapter agrees with mean corneal thickness measured with the Tandem Scanning confocal microscope when both instruments are correctly calibrated.[5] HRT-II/Rostock Cornea Module has 63× lens and optional 10 × to see deeper (lens, zonules), uses a 670 nm diode laser and provides 1 micron resolution. HRT-II/Rostock Cornea Module does applanate cornea and the use of PMMA disposabel cap and gel is mandatory for the exam.[6]

Characteristic Features of IVCM Images

The HRT Rostock Cornea Module is a contact lens system attached to the Heidelberg Retina Tomograph (II) and features three unique imaging modes for maximum versatility: section scan, volume scan, and a sequence scan. A section scan is a single image. Volume scan acquires multiple images from a user-selected starting depth. A sequence scan is a dynamic movie of 1-30 frames of variable depth.[7] Images acquired via LSCM (laser scanning confocal microscopy) are en-face, i.e. parallel to the surface of the cornea, have a field of view of either 300×300 μm or 400×400 μm (depending on the internal lens power) with the lateral resolution of 1-2 μm and the axial resolution of 4 μm. Images taken with slit-scanning microscope (Confoscan Series) have the following parameters: 1-2 μm for lateral and 25-27 μm for axial resolution.[8] The LSCM operator can manually select the depth of interest and adjust the image brightness. The IVCM has the advantage of imaging through moderately opaque tissues ( scarring or edema of the cornea) and also observes the dynamic process in the cornea, i.e. inflammatory reaction monitoring in infectious keratitis, wound healing after refractive surgery. [9][10]

Indications

IVCM Application In Different Ocular Surface Conditions
1. Normal Central Cornea (ageing, contact lens wear-related changes)
2. Dry Eye Disease
3. Corneal ectatic disorders, dystrophies, degenerations
4. ICE syndromes
5. Keratitis (microbial, fungal, parasitic, viral)
6. Post-surgical evaluation of the cornea ( cataract surgery, LASIK, LASEK , PRK, keratoplasties )
7. Corneal deposits ( pseudoexfoliation syndrome, drug-induced )
8. Systemic diseases ( DM, Parkinson's disease, SLE, RA )
9. Evaluation of the conjunctivitis ( conjunctivitis, neoplasia )
10. Limbal Stem Cell Deficiency ( chemical or thermal injury, Stevens-Johnson syndrome )
11. Ocular neuropathic pain
12. Neurotrophic keratitis

The use of IVCM in the scientific research has been expanding rapidly over the past years. It has also been implemented for the clinical diagnosis of different ocular surface conditions as well as a screening tool for patients undergoing treatment.

Description of Corneal Epithelium

The superficial layer is difficult to image by IVCM. It is comprised of superficial epithelial cells, wing cells and basal epithelial cells. The superficial cells are usually 40-50 μm in diameter with hyper-reflective cytoplasm and a bright nuclei of 10 μm. [11] The wing cells are 20-30 μm in diameter with very thin borders and the average wing cell density is 5000 cell/mm².[12] Basal epithelial cells have a smaller diameter of 8-10 μm with dark cytoplasm and bright borders. They show honeycomb pattern and variable cell densities among studies-from 3600 to 8996 cell/mm².[12][13] IVCM has demonstrated a decrease in basal epithelial cell density in diabetic patient population.[14]

Hyper-reflective dendritic structures have been documented at the level of the basal epithelium and Bowman's membrane in 12-30% of normal volunteers with a mean density of 34 ± 3 cell/mm² in the central cornea and 98 ± 8 cell/mm² in the periphery.[15] Langerhans cells (LCs) are professional antigen presenting cells of the ocular surface and can be detected in the normal, un-inflamed cornea.[16] Increased density of LCs have been detected in the central cornea of patients with keratoconjunctivitis.[17][18]

Description of Bowman's layer

It is an amorphous 10 μm thick membrane posterior to the basal epithelium, featureless and grey on confocal microscopic images with discrete nerves bundles in the field of view. Some keratocytes may be seen in the background.

Description of Corneal Stroma

Stroma is composed of collagen fibers, keratocytes and interstitial substance. Keratocyte nuclei are 5-30 μm in diameter, have a bean-like shape in the anterior stroma and are oval posteriorly. Myelinated nerve fibers can be visualized in the anterior stroma, but the orientation and size are variable which makes quantification difficult. A study showed that stromal thickness imaged by IVCM was significantly higher in diabetic patients.[19] Keratocyte density is the highest in the anterior stroma, 50-100 μm posterior to the Bowman's membrane.[20] Confocal microscopy has been used to show keratocyte density in normal cornea, contact lens wearers, keratoconus etc.[21][22]

Description of Descemet's membrane

Images of Descemet's membrane have a hazy appearance. It is 6-10  μm thick with cellular structures not identifiable on IVCM images. Normal Descemet's membrane is not visible when imaged by IVCM in young people, but becomes more visible with aging.[23]

Description of Endothelium

This is a layer of cells that are 4-6 μm thick and 20 μm in diameter with a hexagonal or polygonal shape. On IVCM, they are identified as bright cell bodies with dark cell borders. The nuclei are rarely recognizable. Increasing age cases a reduction in endothelial cell density by approximately 0.6% per year and increase in cell variation.[24] In studies using (HRT-II)/Rostock Cornea Module (RCM) (Heidelberg Engineering GmbH, Heidelberg,Germany) the average endothelial cell density varied between 2550 and 2720 cell/mm².[25] Diabetic patients show an increase in endothelial cell damage and polymegathism with increasing duration of diabetes.[26][27]

Corneal Nerves

Nerves enter the cornea from a peripheral, mid-stromal depth and proceed anteriorly terminating between corneal epithelial cells. These nerves loose their myelin sheath within 1 mm of the limbus and are subsequently surrounded by Schwann cell sheaths.[28] Nerves bundles from anterior stroma penetrate through Bowman's membrane to form sub-basal nerve plexus that runs parallel to the ocular surface.[4] Corneal nerves are easily identified by IVCM. Sub-basal corneal nerves are hyper-reflective linear structures. The sub-basal nerve diameter can vary from 0.52 μm to 4.6 μm.[29] Sub-basal nerve density values vary between studies mainly due to different types of confocal microscopes used for imaging. Nerve density values reported from studies using HRTII RCM are higher than values reported from studies using slit scanning confocal microscopes: 21.6 mm/mm² [8] via HRTII RCM vs. 15.18 mm/mm² via slit scanning microscope. [30] Nerve fiber bundles are arranged radially in cornea and converge toward 1-2 mm inferior to the central cornea to form whorl or vortex pattern.

Stromal nerves can be divided into 2 groups: sub-Bowman's and mid-stromal nerves. Sub-Bowman zone appear as hyper-reflective linear 1-5μm thick structure. The thicker mid-stromal nerves run straight and show dichotomous bifurcation. Corneal nerves can be analyzed qualitatively and quantitatively by IVCM. Physicians can thus explore corneal innervation after keratoplasty, PRK, LASIK, dry eye, and diabetic neuropathy.[31] However, one study highlighted the importance of experienced observers in the manual assessment of corneal nerve parameters.[32]

Description of Conjunctiva

Normal bulbar conjunctival epithelium is comprised of superficial, intermediate and basal cells. Large, hypo reflective oval-shaped cells are also seen throughout the epithelium. Those cells represent the goblet cell population in the conjunctival epithelium. Goblet cells constitute approximately 10% of the conjunctival epithelial cell population and they are scattered in the conjunctival epithelium.[33] Conjunctival epithelium also contains LC, which function as tissue macrophages. Epithelial cells in the palpebral conjunctiva are much smaller than those of the bulbar conjunctival epithelium. At the corneal limbus, the conjunctival epithelium and the stroma form palisades of Vogt. IVCM has been also used to study the inflamed conjunctiva in different types of conjunctivitis. The common feature is that the inflammatory cells are significantly increased in epithelium and the stromal collagen meshwork contains hyper-reflective debris as well.[34] The episclera and sclera are too deep to be visualized by IVCM.

IVCM may help to identify suspicious conjunctival lesions, but it does not replace histology for the diagnosis of the tumors.

Procedure

Heidelberg Retinal Tomograph 3 with Rostock Cornea Module (HRT3-RCM): Application in the clinic

Patient examination in the clinic is conducted over anesthetized cornea and may last from 5-15 min with patient rarely experiencing discomfort. The system consists of 670 nm diode laser and horizontally-mounted optics upon which a disposable plastic sterile cap is placed (Tomo-Cap; Heidelberg Engineering GmbH). The cap comes in touch with the corneal surface through a refractive index-matching ophthalmic gel (Comfort Gel; Bausch & Lomb GmbH, Berlin, Germany). For confocal imaging, the ophthalmic gel is placed on the tip of objective lens to serve as a cushion and to eliminate bright reflections. Scans are collected from epithelium to endothelium while using the (HRT3-RCM) streaming software function. The acquisition rate for sequence scans can be set to 30 frames/second and up to 100 images can be stored. Image acquisition of 8 frames/sec is typical for patients without nystagmus. In order to obtain good images, the patient's corneal surface has to be in good contact with the objective lens. This often requires manual manipulation of head and eyelids. Access to cornea layers further from the apex is achieved by manually placing a fixation target into which the patient is instructed to view.[35] A digital camera mounted on a side provides a lateral view of the eye and objective lens, which helps monitor the position of the lens on the ocular surface during the examination.

Potential complications of this procedure include corneal abrasion and infection. Careful disinfection of the lens surface is important to minimize the risk. The risk of corneal abrasions may be higher in patients with epithelial defects, ulcers and corneal epithelial or basement membrane dystrophies.

IVCM Findings in Contact Lens Wearers

The availability of confocal microscopy in the clinic provides an opportunity to study cornea changes after contact lens wear. Confocal microscopy can be performed over the contact lens to observe changes in corneal cellular morphology. Studies have shown that contact lens wear causes stromal acidosis and hypoxia.[36][37] However, long-term contact lens wear and its associated acidosis and hypoxia have no significant effect on keratocyte density. Decreased corneal sensitivity in contact lens wearers is not associated with decreased nerve fiber bundle density, either.[38] Various studies have shown that extended contact lens wear does cause a loss of keratocytes.[39][40] The effects of contact lens wear on the bulbar conjunctiva can be investigated by LSCM as well. When a soft contact lens is worn, it completely covers the cornea and impinges 2 mm onto the bulbar conjunctiva. During eye movement or blinking, contact lenses can be displaced and impinge further onto the bulbar conjunctiva. Both the cornea and conjunctiva are susceptible to physical irritation from the lens. The observation in one study suggests that contact lens wear induces conjunctival epithelial thinning, accelerates formation of microcysts, increases epithelial cell density, but has no impact on Langerhans or goblet cell density.[41] Also in contact lens wearers LC density in central and peripheral parts of cornea has been reported to be twofold higher than in normal controls, implying mechanical irritation of the corneal surface .[42] The mechanical irritation from contact lens wear either soft or rigid may promote inflammatory mediators (cytokines, growth factors) release and keratocyte redistribution in corneal stroma.[43]

IVCM and Limbal Stem Cell Deficiency

The corneal limbus is a semitransparent, vascularized transition zone between cornea and sclera. The palisades of Vogt are believed to harbor corneal epithelial stem cells and are distinctive normal features of the human corneoscleral limbus. The palisades of Vogt were first clinically described in 1914 by Streiff who called them radial stripes. They are a series of radially oriented fibrovascular ridges and in between them there is a thickened conjunctival epithelium or so-called interpalisades. In vivo confocal microscopy is useful in observing limbal microstructures. Clusters of hyperreflective structures were observed in the anterior limbal stroma , but not in the corneal stroma.[44] Stem cells of the corneal epithelium reside in the basal limbal part of the corneoscleral junction. Deficiency of these epithelial stem cells can be either inherited (aniridia, multiple endocrine deficiency, epidermal dysplasia) or acquired (burns, cicatricial pemphigoid, Stevens-Johnson syndrome, contact lens-associated, neurotrophic keratopathy, multiple surgeries, chronic limbitis, severe microbial infections extending to limbus). Live imaging of corneolimbal epithelial architecture became possible with the advent of in vivo confocal microscopy. In cases of limbal stem cell deficiency, the limbal epithelium is replaced by conjunctival epithelium characterized by cells with or without evident nuclei, along with goblet cells (which are characterized by large oval hyper-reflective cells). Large numbers of dendritic cells are also present in the conjunctival epithelium, mostly in the subepithelial region. The Bowman layer can not be identified and the stroma has fewer keratocytes when compared with a normal cornea .[45] Corneal basal cell density along with subbasal nerve plexus density decreases in patients with limbal stem cell deficiency and basal epithelial cells become severely metaplastic.[46][47] Analysis of the limbal stroma showed replacement of hyper-reflecive niche structures by bright fibrotic structures.[46]

The diagnosis of LSCD is mostly clinical with definitive changes observed by slit-lamp biomicroscopy, but there is some limitation with this technique associated with subtle changes, particularly in partial LSCD. Superficial corneal neovascularization, conjunctivalization and ocular surface inflammation are often subtle and nonspecific in partial LSCD. Impression cytology (IC) analysis can also provide objective evidence of LSCD, but it does not offer analysis on deeper corneal layers. IVCM is more reliable diagnostic technique in patients with the suspected diagnosis of LSCD and it showed a substantial degree of concordance with IC analysis.[48][49] IVCM is a useful tool and may be more reliable than IC analysis in evaluation of outcomes after limbal stem cell transplantation in the long term as well.[48]

ICVM and Keratoconus

Keratoconus is a progressive noninflammatory corneal ectasia in which the cornea assumes a conical shape. It is characterized by stromal thinning that may be the result of a loss of keratocytes, extracellular matrix, or both.[50] Investigators showed good repeatability and reproducibility for keratocyte count by LSCM.[51] In subjects with keratoconus ICVM showed a significant reduction in keratocyte cell count, a decline that was correlated with indices of disease severity. Anterior keratocyte density was significantly lower in contact lens-wearing keratoconic subjects.[52] Morphologic alterations to the epithelium and Bowman's layer have also been described, such as disruption of Bowman's layer and the occasional presence of epithelial cells and keratocytes. Most of the changes observed with CM have been correlated with the findings obtained by light microscopy.[53]

Corneal cross linking has been shown to reduce the progression of keratoconus and potentially avoid the need for keratoplasty. Reduction in anterior and intermediate keratocytes followed by gradual repopulation has been  described by HRT II-RCM confocal microscopy after riboflavin-UVA-induced corneal collagen cross-linking.[54] IVCM has also been successfully used to characterize keratoconic cornea after deep anterior lamellar keratoplasty (DALK) and penetrating keratoplasty (PKP). Images obtained by Confoscan P4 ( Nidek Technology, Padova, Italy) confirmed that keratocyte density was significantly lower in the DALK group than in the PKP group throughout the stroma. One of the possible mechanisms of such cellular changes of the donor tissue could be the mechanical trauma to the donor tissue during the surgery.[55] [56]

Confocal microscopy enables evaluation of corneal microstructural changes in patients with manifest keratoconus (KCN), subclinical KCN and in topographically normal KCN relatives. This technique is useful for the determination of early corneal changes before the manifestation of topographic signs.[57]

ICVM in Corneal Dystrophies

Corneal dystrophies are a group of inherited disorders that are usually bilateral, symmetric, slowly progressive and not related to environmental or systemic factors.[58] Disorders in this group can affect various corneal layers resulting in certain micro-structural as well as gross morphological changes. Confocal microscopy can visualize the changes non-invasively at a cellular level. This technique has been used to delineate changes in posterior polymorphous corneal dystrophy (PPCD), Fuchs' endothelial dystrophy, bowman and stromal corneal dystrophies. In a case series of patients with PPCD, confocal microscopy showed reduced endothelial cell density, hyperreflectivity at the level of Descemet's membrane surrounding the endothelial lesions, which have been classified into 3 main forms: vesicular, band and diffuse.[59]

Confocal microscopy performed in eyes with Reis–Buckler dystrophy, granular dystrophy and lattice type-I dystrophy demonstrated a diversity of a deposit pattern among these three autosomal-dominant corneal dystrophies.[60] In this case series epithelium was involved in 30% of the eyes and stroma was involved in all eyes. Some of the confocal findings near the Bowman membrane were common for all three dystrophies.[60] This technique may be used in addition to slit-lamp biomicroscopy in atypical corneal dystrophies, as histopathologic studies cannot be obtained systematically for all patients affected. In lattice corneal dystrophy linear and branching structures with changing reflectivity were visualized in the stroma.[61] In Fleck and pre-Descemet's membrane corneal dystrophy, IVCM found intracellular deposits throughout the stroma.[62]

Anterior corneal cellular and structural abnormalities begin early in the course of Fuch's dystrophy, before the onset of clinically evident edema. IVCM demonstrated depletion of anterior stromal cells and high extracellular reflectivity even in patients with mild cases of Fuch's dystrophy. IVCM images visualized reticular networks of probably fibroblasts located deep to the basal epithelial layer that were highly reflective, hence contributing to corneal backscatter and irregular anterior corneal surface.[63] This subclinical changes are relevant for postoperative visual outcomes after introduction of newer surgical techniques like DSEK.[64]

IVCM in Systemic Diseases

IVCM is a non-invasive method that has been proposed to diagnose as well as to assess the progression of diabetic neuropathy. It enables the study of corneal nerve alterations in various ocular diseases, after corneal surgery and in systemic diseases. The correlation between reduced corneal nerve bundles with loss of corneal sensation and severity of somatic neuropathy has been shown in patients with type 1 diabetes.[65] IVCM detects early peripheral neuropathy and also shows that corneal nerves recover with improved glycemic control withing 6 months after pancreatic transplantation in diabetic patients.[66]

It is a valuable technique to visualize immunoprotein deposits as well as to determine the extent of corneal involvement in gammopathies. The immunoprotein crystals related to IgG-kappa gammopathy could be found in the epithelium. In contrast, the MGUS immunoprotein deposits associated with IgA-gammopathy involved the anterior and mid-stroma with sparing of the epithelium and endothelial layers. Endothelium has not been involved in this case series.[67]

Fabry disease is an X-linked genetic disorder determined by the deficient activity of α galactosidase A, a lysosomal enzyme, that causes an error in glycosphingolipid metabolism. Cornea verticillata and stromal haze are the most characteristic and frequent ocular findings of this disorder. Confocal microscopy has been utilized to describe microscopic corneal and conjunctival findings in patients with Fabry disease (FD) related keratopathy. Structural alterations were found throughout the entire ocular surface epithelium. IVCM could be a a useful technique in facilitating the diagnosis of FD-related ocular surface manifestation and to detect variations while monitoring the effect of enzyme replacement therapy in the future.[68]

In Vivo Confocal Microscopy After Ocular Surgery

IVCM in Refractive Surgery

Laser in situ keratomileusis (LASIK) is a leading technique in refractive vision correction. IVCM helps clinicians to examine flap-related complications after refractive surgeries and describe changes in corneal nerves and sublayers.[69] This technique images small particles at the flap interface as well as Bowman layer's microfolds.[69]

IVCM as a high resolution imaging modality can assess and compare corneal modifications caused by different types of lasers used to create LASIK flap.[70] Some studies showed that LASIK with IntraLase provides more reproducible flap thickness and fewer interface particles.[70][71] Interface particle could be either metal or plastic particles from the microkeratome blade or lipid products, migrated corneal epithelial cells, synthetic material such as sponge particles, powder from surgical gloves, or inflammatory cells.[72][73]

Studies of in vivo confocal microscopy after LASIK have shown that the number of sub-basal and stromal nerve fiber bundles decreased by more than 90% 1 week after LASIK and increased from 3 months to 1 year after surgery.[69][74][75]

After photorefractive keratectomy (PRK), IVCM shows the regeneration of the epithelium covering the wound. Activated keratocytes that are responsible for the clinically visible haze could be evaluated objectively with this technique.[76] Another study described corneal wound healing after myopic PRK and showed that epithelial thickness increased 21% by 12 months and remained unchanged to 36 months after PRK, but there was no change in stromal thickness between 1 and 36 months after PRK. Activated keratocytes and corneal haze peaked at 3 months after myopic PRK.[77]

ICVM showed that increase in corneal epithelial thickness after myopic LASIK persists for at least 7 years and that the central corneal thickness increases during the first year after PRK and remains stable thereafter up to 7 years.[78]

IVCM in the Management of Microbial Keratitis

Microbial keratitis is a major blinding eye disease in the world and is more common in contact lens wearers. IVCM proved to be a useful tool in the early diagnosis of microbial keratitis, and particularly in fungal and Acanthamoeba keratitis (AK). Delayed diagnosis of these infections is common due to the time delay of corneal cultures and slow-growing fungi and Acanthamoeba. A fast and reliable diagnosis of Acanthamoeba and fungal keratitis is essential to ensure an optimal outcome.

Acathamoeba is a ubiquitous protozoan found in water, soil, air and has a 2-stage life cycle: trophozoites and cysts. Both of these forms are identifiable on IVCM exam along with corneal nerves and inflammatory cells.[79] Acanthamoeba cysts are hyper-reflective 15-28 micrometers in size with a double wall. They are usually spherical, but may sometimes appear ovoid. The trophozites are usually 25-40 micrometers in diameter, also hyper-reflective with surrounding hypo-reflective edema.[79]

IVCM can also be used to measure the depth of cysts invasion and to monitor the progression and response to the antimicrobial therapy. Numerous studies described cyst morphology in AK, and a few analyzed the arrangement of these structures. Cysts can be organized in chains and/or clusters [80] or have "single file arrangement"[81]. Interestingly, the arrangement of Acanthamoeba cysts in clusters or chains was associated with a worse outcome of AK [80]. IVCM had a sensitivity of 90% and specificity of 100% in case of both clinical and objective evidence of AK.[82] Numerous studies have demonstrated usefulness of IVCM for the diagnosis of AK.

Heidelberg Retina Tomograph Rostock Cornea Module- HRT III RCM has advantage of imaging corneal structures with much higher resolution. Its magnification (800 ×) is high enough to visualize fungal hyphae and yeast in the cornea. The high resolution allows visualization of yeasts, which has never been described with previous confocal microscopes.

Fusarium hyphae and Candida pseudo filaments were imaged by HRTII‐RCM [83] . The Fusarium solani patients' corneas revealed numerous high‐contrast lines 200–300 μm in length and 3–5 μm in width with branches at 90° angles. Candida albicans-infected corneas revealed numerous high‐contrast elongated particles measuring 10–40 μm in length and 5–10 μm in width, resembling pseudo filaments. In all fungal keratitis cases inflammatory cells were present at the epithelial layer. IVCM is a valuable tool in diagnosing filamentous fungal keratitis and clinically applicable grading scale could facilitate the interpretation of the IVCM images[84].

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  28. ↑ Linda J. Müller, Carl F. Marfurt, Friedrich Kruse, Timo M.T. Tervo Erratum to “Corneal nerves: structure, contents and function” by L.J. Müller, C.F. Marfurt, F. Kruse and T.M.T. Tervo[Exp. Eye Res. 76 (2003) 521–542] Experimental Eye Research, Volume 77, Issue 2, August 2003, Page 253
  29. ↑ Mitra Tavakoli,1 Parwez Hossain,2 and Rayaz A Malik1 Clin Ophthalmol. 2008 Jun; 2(2): 435–445. PMCID: PMC2693976 Clinical applications of corneal confocal microscopy
  30. ↑ Zhang M1, Chen J, Luo L, Xiao Q, Sun M, Liu Z. Cornea. 2005 Oct;24(7):818-24. Altered corneal nerves in aqueous tear deficiency viewed by in vivo confocal microscopy.
  31. ↑ Hu L1, Xie W, Tang L, Chen J, Zhang D, Yu P, Qu J2. Zhonghua Yan Ke Za Zhi. 2015 Jan;51(1):39-44.[Corneal subbasal nerve density changes after laser in situ keratomileusis with mechanical microkeratome and femtosecond laser].
  32. ↑ Petropoulos, Ioannis N. MSc*,†; Manzoor, Tauseef MBChB*; Morgan, Philip PhD‡; Fadavi, Hassan MD*,†; Asghar, Omar MBChB*,†; Alam, Uazman MBChB, MPH*,†; Ponirakis, Georgios MPhil*,†; Dabbah, Mohammad A. PhD§; Chen, Xin PhD§; Graham, James PhD§; Tavakoli, Mitra PhD*,†; Malik, Rayaz A. MBChB, FRCP, PhD*,†Cornea:May 2013 - Volume 32 - Issue 5 - p e83–e89doi: 10.1097/ICO.0b013e3182749419Repeatability of In Vivo Corneal Confocal Microscopy to QuantifyCorneal Nerve Morphology
  33. ↑ Kobayashi, Akira MD, PhD; Yoshita, Tsuyoshi MD; Sugiyama, Kazuhisa MD, PhD Cornea:November 2005 - Volume 24 - Issue 8 - pp 985-988In Vivo Findings of the Bulbar/Palpebral Conjunctiva and Presumed Meibomian Glands by Laser Scanning ConfocalMicroscopy
  34. ↑ Messmer, Elisabeth M MD; Mackert, Marc J; Zapp, Daniel M; Kampik, Anselm MD Cornea:August 2006 - Volume 25 - Issue 7 - pp 781-788doi: 10.1097/01.ico.0000224648.74095.90 In Vivo Confocal Microscopy of Normal Conjunctiva and Conjunctivitis
  35. ↑ Neil Lagali1, Beatrice Bourghardt Peebo1, Johan Germundsson1, Ulla Edén1, Reza Danyali1, Marcus Rinaldo1 and Per Fagerholm1  Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden. Laser-Scanning in vivo Confocal Microscopy of the Cornea: Imaging and Analysis Methods for Preclinical and Clinical Applications. Chapter 4.
  36. ↑ Brennan NA, Efron N, Carney LG. Corneal oxygen availability during contact lens wear: a comparison of methodologies. Am J Optom Phys Opt. 1988;65:19–24Bonanno JA, Polse KA. Effect of rigid contact lens oxygen trans- missibility on stromal pH in the living human eye. Ophthalmology. 1987;94:1305–1309.
  37. ↑ Bonanno JA, Polse KA. Effect of rigid contact lens oxygen trans- missibility on stromal pH in the living human eye. Ophthalmology. 1987;94:1305–1309.
  38. ↑ Patel SV1, McLaren JW, Hodge DO, Bourne WM. Invest Ophthalmol Vis Sci. 2002 Apr;43(4):995-1003.Confocal microscopy in vivo in corneas of long-term contact lens wearers.
  39. ↑ Efron N1, Perez-Gomez I, Morgan PB. Clin Exp Optom. 2002 May;85(3):156-60.Confocal microscopic observations of stromal keratocytes during extended contact lens wear.
  40. ↑ Efron N1, Mutalib HA, Perez-Gomez I, Koh HH. Clin Exp Optom. 2002 May;85(3):149-55. Confocal microscopic observations of the human cornea following overnight contact lens wear.
  41. ↑ Efron, Nathan PhD, DSc*†; Al-Dossari, Munira M App Sc*†; Pritchard, Nicola B App Sc (Optom)*† Cornea:January 2010 - Volume 29 - Issue 1 - pp 43-52 Confocal Microscopy of the Bulbar Conjunctiva in Contact LensWear
  42. ↑ Zhivov, Andrey MD*; Stave, Joachim PhD*; Vollmar, Brigitte MD†; Guthoff, Rudolf MD* Cornea:January 2007 - Volume 26 - Issue 1 - pp 47-54 doi: 10.1097/ICO.0b013e31802e3b55 In Vivo Confocal Microscopic Evaluation of Langerhans Cell Density and Distribution in the Corneal Epithelium of Healthy Volunteers and Contact Lens Wearers
  43. ↑ Kallinikos, Panagiotis PhD; Morgan, Philip PhD; Efron, Nathan PhD, DSc Cornea: January 2006 - Volume 25 - Issue 1 - pp 1-10 Assessment of Stromal Keratocytes and Tear Film Inflammatory Mediators During Extended Wear of Contact Lenses
  44. ↑ Mathews, Saumi MSc, MPhil*; Chidambaram, Jaya Devi MD, MRCOphth†; Lanjewar, Shruti MS‡; Mascarenhas, Jeena MS‡; Prajna, Namperumalsamy Venkatesh DNB, FRCOph‡; Muthukkaruppan, Veerappan PhD§; Chidambaranathan, Gowri Priya PhD* Cornea:January 2006 - Volume 25 - Issue 1 - pp 1-10 Assessment of Stromal Keratocytes and Tear Film Inflammatory Mediators During Extended Wear of Contact Lenses
  45. ↑ Chidambaranathan, Gowri Priya PhD; Mathews, Saumi MSc, MPhil; Panigrahi, Arun Kumar MS; Mascarenhas, Jeena MS; Prajna, Namperumalsamy Venkatesh DNB, FRCOph; Muthukkaruppan, Veerappan PhD Cornea: In vivo Confocal Microscopic Analysis of Limbal Stroma in Patients With Limbal Stem Cell Deficiency
  46. ↑ 46.0 46.1 Deng SX1, Sejpal KD, Tang Q, Aldave AJ, Lee OL, Yu F. Arch Ophthalmol. 2012 Apr;130(4):440-5. doi: 10.1001/archophthalmol.2011.378. Epub 2011 Dec 12. Characterization of limbal stem cell deficiency by in vivo laser scanning confocal microscopy: a microstructural approach.
  47. ↑ Chan EH1, Chen L2, Rao JY3, Yu F4, Deng SX5. Limbal Basal Cell Density Decreases in Limbal Stem Cell Deficiency. Am J Ophthalmol. 2015 Oct;160(4):678-684.e4. doi: 10.1016/j.ajo.2015.06.026. Epub 2015 Jul 4.
  48. ↑ 48.0 48.1 Pedrotti E1, Passilongo M2, Fasolo A3, Nubile M4, Parisi G2, Mastropasqua R5, Ficial S2, Bertolin M6, Di Iorio E7, Ponzin D6, Marchini G2. Ophthalmology. 2015 Aug;122(8):1660-8. doi: 10.1016/j.ophtha.2015.04.004. Epub 2015 Jun 4. In Vivo Confocal Microscopy 1 Year after Autologous Cultured Limbal Stem Cell Grafts.
  49. ↑ Nubile M1, Lanzini M, Miri A, Pocobelli A, Calienno R, Curcio C, Mastropasqua R, Dua HS, Mastropasqua L. Am J Ophthalmol. 2013 Feb;155(2):220-32. doi: 10.1016/j.ajo.2012.08.017. Epub 2012 Nov 3. In vivo confocal microscopy in diagnosis of limbal stem cell deficiency.
  50. ↑ Kim WJ, Rabinowitz YS, Meisler DM, Wilson SE. Keratocyte apoptosis associated with keratoconus. Exp Eye Res 1999;69: 475– 81.
  51. ↑ Niederer RL, Perumal D, Sherwin T, McGhee CN. Repeatability and reproducibility of the Heidelberg Retina Tomograph II Rostock Corneal Module laser scanning in vivo confocal microscope. Graefes Arch Clin Exp Ophthalmol. In press.
  52. ↑ Judy Y.F. Ku, Rachael L. Niederer, Dipika V. Patel, Trevor Sherwin, Charles N.J. McGhee Ophthalmology, Vol. 115, Issue 5, p845–850 Laser Scanning In Vivo Confocal Analysis of Keratocyte Density in Keratoconus
  53. ↑ Hollingsworth, Joanna G PhD, MCOptom*; Bonshek, Richard E MD, FRCPath†; Efron, Nathan DSc, MCOptom* Cornea:May 2005 - Volume 24 - Issue 4 - pp 397-405 Correlation of the Appearance of the Keratoconic Cornea In Vivo by Confocal Microscopy and In Vitro by Light Microscopy
  54. ↑ Mazzotta, Cosimo PhD*; Balestrazzi, Angelo PhD*; Traversi, Claudio MD*; Baiocchi, Stefano PhD*; Caporossi, Tomaso MD†; Tommasi, Cristina MD*; Caporossi, Aldo MD* Cornea:May 2007 - Volume 26 - Issue 4 - pp 390-397 Treatment of Progressive Keratoconus by Riboflavin-UVA-Induced Cross-Linking of Corneal Collagen: Ultrastructural Analysis by Heidelberg Retinal Tomograph II In Vivo Confocal Microscopy in Humans
  55. ↑ Feizi, Sepehr MD; Javadi, Mohammad Ali MD; Kanavi, Mozhgan Rezaei MD Cornea:August 2010 - Volume 29 - Issue 8 - pp 866-870 Cellular Changes of Donor Corneal Tissue After Deep Anterior Lamellar Keratoplasty Versus Penetrating Keratoplasty in Eyes With Keratoconus: A Confocal Study
  56. ↑ Farias R, Barbosa L, Lima A, et al. Deep anterior lamellar transplant using lyophilized and Optisol corneas in patients with keratoconus. Cornea. 2008;27:1030-1036.
  57. ↑ Engin Bilge Ozgurhan, Necip Kara, Aydin Yildirim, Ercument Bozkurt, Hasim Uslu, Ahmet Demirok American Journal of Ophthalmology, Vol. 156, Issue 5, p885–893.e2 Published online: August 7 2013 Evaluation of Corneal Microstructure in Keratoconus: A Confocal Microscopy Study
  58. ↑ Afshari NA, Bouchard CS, Colby KA, de Freitas D, Rootman DS, Tu EY, Weisenthal RW. Corneal dystrophies and ectasias. In: Weisenthal RW, ed. 2014–2015 Basic and Clinical Science Course, Section 8: External Disease and Cornea. San Francisco; American Academy of Ophthalmology; 2014:253–287.
  59. ↑ Patel, Dipika V; Grupcheva, Christina N; McGhee, Charles N. Cornea. 24(5):550-554, July 2005. In Vivo Confocal Microscopy of Posterior Polymorphous Dystrophy
  60. ↑ 60.0 60.1 Werner LP1, Werner L, Dighiero P, Legeais JM, Renard G. Ophthalmology. 1999 Sep;106(9):1697-704. Confocal microscopy in Bowman and stromal corneal dystrophies.
  61. ↑ Chiou AG1, Beuerman RW, Kaufman SC, Kaufman HE. Graefes Arch Clin Exp Ophthalmol. 1999 Aug;237(8):697-701. Confocal microscopy in lattice corneal dystrophy.
  62. ↑ Holopainen, Juha M. M.D.; Moilanen, Jukka A.O. M.D.; Tervo, Timo M.T. M.D. Cornea:March 2003 - Volume 22 - Issue 2 - pp 160-163 In Vivo Confocal Microscopy of Fleck Dystrophy and Pre-Descemet's Membrane Corneal Dystrophy
  63. ↑ Sejal R. Amin, Keith H. Baratz, Jay W. McLaren, Sanjay V. Patel Ophthalmology, Vol. 121, Issue 12, p2325–2333 Corneal Abnormalities Early in the Course of Fuchs' Endothelial Dystrophy
  64. ↑ Hecker LA, McLaren JW, Bachman LA, Patel SV. Anterior keratocyte depletion in Fuchs’ endothelial dystrophy. Arch Ophthalmol 2011;129:555–61.
  65. ↑ Rosenberg ME, Tervo TM, Immonen IJ, Müller LJ, Grönhagen-Riska C, Vesaluoma MH Corneal structure and sensitivity in type 1 diabetes mellitus. Invest Ophthalmol Vis Sci. 2000 Sep; 41(10):2915-21
  66. ↑ Mehra S, Tavakoli M, Kallinikos PA, Efron N, Boulton AJ, Augustine T, Malik RA Corneal confocal microscopy detects early nerve regeneration after pancreas transplantation in patients with type 1 diabetes. Diabetes Care. 2007 Oct; 30(10):2608-12.
  67. ↑ Sibel Kocabeyoglu, Mehmet C Mocan, Ibrahim C Haznedaroglu,1 Aysegul Uner,2 Enes Uzunosmanoglu, and Murat Irkec In vivo confocal microscopic characteristics of crystalline keratopathy in patients with monoclonal gammopathy: Report of two cases Indian J Ophthalmol. 2014 Sep; 62(9): 938–940.
  68. ↑ Leonardo Mastropasqua, Mario Nubile, Manuela Lanzini, Paolo Carpineto, Lisa Toto, Marco Ciancaglini Corneal and Conjunctival Manifestations in Fabry Disease: In Vivo Confocal Microscopy Study American Journal of Ophthalmology, Vol. 141, Issue 4, p709–709.e11
  69. ↑ 69.0 69.1 69.2 Perez-Gomez I, Efron N. Change to corneal morphology after refractive surgery (myopic laser in situ keratomileusis) as viewed with a confocal microscope. Optom Vis Sci 2003; 80: 690–697.
  70. ↑ 70.0 70.1 Sonigo B1, Iordanidou V, Chong-Sit D, Auclin F, Ancel JM, Labbé A, Baudouin C. In vivo corneal confocal microscopy comparison of intralase femtosecond laser and mechanical microkeratome for laser in situ keratomileusis. Invest Ophthalmol Vis Sci. 2006 Jul;47(7):2803-11.
  71. ↑ James P. McCulley, MD* and W. Matthew Petroll, PhD Quantitative Assessment of Corneal Wound Healing Following IntraLASIK Using In Vivo Confocal Microscopy Trans Am Ophthalmol Soc. 2008 Dec; 106: 84–92.
  72. ↑ Perez-Gomez I, Efron N. Confocal microscopic evaluation of particles at the corneal flap interface after myopic laser in situ keratomileusis. J Cataract Refract Surg. 2003;29:1373–1377.
  73. ↑ Ivarsen A, Thogersen J, Keiding SR, Hjortdal JP, Moller-Pedersen T. Plastic particles at the LASIK interface. Ophthalmology. 2004;111: 18 –23.
  74. ↑ Vesaluoma M, Perez-Santonja J, Petroll WM, Linna T, Alio J, Tervo T. Corneal stromal changes induced by myopic LASIK. Invest Ophthalmol Vis Sci. 2000;41:369 –376.
  75. ↑ Calvillo MP, McLaren JW, Hodge DO, Bourne WM. Corneal reinnervation after LASIK: prospective 3-year longitudinal study. Invest Ophthalmol Vis Sci. 2004;45:[[1]].
  76. ↑ Moilanen JA1, Vesaluoma MH, Müller LJ, Tervo TM. Long-term corneal morphology after PRK by in vivo confocal microscopy. Invest Ophthalmol Vis Sci. 2003 Mar;44(3):1064-9.
  77. ↑ Jay C Erie Corneal wound healing after photorefractive keratectomy: a 3-year confocal microscopy study. Trans Am Ophthalmol Soc. 2003; 101: 293–333.
  78. ↑ Patel SV1, Erie JC, McLaren JW, Bourne WM. Confocal microscopy changes in epithelial and stromal thickness up to 7 years after LASIK and photorefractive keratectomy for myopia. J Refract Surg. 2007 Apr;23(4):385-92.
  79. ↑ 79.0 79.1 Labbe A, et al. Contribution of in vivo confocal microscopy to the diagnosis and management of infectious keratitis.  The Ocular Surface. 2009;7:41–52
  80. ↑ 80.0 80.1 Zhang X1, Sun X2, Jiang C1, Wang Z1, Zhang Y1, Deng S1, Labbé A3 A new in vivo confocal microscopy prognostic factor in Acanthamoeba keratitis J Fr Ophtalmol. 2014 Feb;37(2):130-7. doi: 10.1016/j.jfo.2013.09.004. Epub 2014 Jan 4.
  81. ↑ Rezaei Kanavi M1, Naghshgar N, Javadi MA, Sadat Hashemi M. Various confocal scan features of cysts and trophozoites in cases with Acanthamoeba keratitis. Eur J Ophthalmol. 2012;22 Suppl 7:S46-50. doi: 10.5301/ejo.5000139.
  82. ↑ Tu E, et al. The relative value of confocal microscopy and superficial corneal scrapings in the diagnosis of acanthamoeba keratitis. Cornea. 2008;27:764–772.
  83. ↑ Emmanuelle Brasnu, Tristan Bourcier, Bénédicte Dupas, Sandrine Degorge, Thibault Rodallec, Laurent Laroche, Vincent Borderie, and Christophe Baudouin In vivo confocal microscopy in fungal keratitis Br J Ophthalmol. 2007 May; 91(5): 588–591.
  84. ↑ E. Nielsen,a,* S. Heegaard,b,c J.U. Prause,b A. Ivarsen,a K.L. Mortensen,d and J. Hjortdala Fungal Keratitis – Improving Diagnostics by Confocal Microscopy Case Rep Ophthalmol. 2013 Sep-Dec; 4(3): 303–310
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