Antoine Labbé

Preservatives in eyedrops: The good, the bad and the ugly

There is a large body of evidence from experimental and clinical studies showing that the long-term use of topical drugs may induce ocular surface changes, causing ocular discomfort, tear film instability, conjunctival inflammation, subconjunctival fibrosis, epithelial apoptosis, corneal surface impairment, and the potential risk of failure for further glaucoma surgery. Subclinical inflammation has also been described in patients receiving antiglaucoma treatments for long periods of time. However, the mechanisms involved, i.e., allergic, toxic, or inflammatory, as well as the respective roles of the active compound and the preservative in inducing the toxic and/or proinflammatory effects of ophthalmic solutions, is still being debated. The most frequently used preservative, benzalkonium chloride (BAK), has consistently demonstrated its toxic effects in laboratory, experimental, and clinical studies. As a quaternary ammonium, this compound has been shown to cause tear film instability, loss of goblet cells, conjunctival squamous metaplasia and apoptosis, disruption of the corneal epithelium barrier, and damage to deeper ocular tissues. The mechanisms causing these effects have not been fully elucidated, although the involvement of immunoinflammatory reactions with the release of proinflammatory cytokines, apoptosis, oxidative stress, as well as direct interactions with the lipid components of the tear film and cell membranes have been well established. Preservative-induced adverse effects are therefore far from being restricted to only allergic reactions, and side effects are often very difficult to identify because they mostly occur in a delayed or poorly specific manner. Care should therefore be taken to avoid the long-term use of preservatives, otherwise a less toxic alternative to BAK should be developed, as this weakly allergenic but highly toxic compound exerts dose- and time-dependent effects. On the basis of all these experimental and clinical reports, it would be advisable to use benzalkonium-free solutions whenever possible, especially in patients with the greatest exposure to high doses or prolonged treatments, in those suffering from preexisting or concomitant ocular surface diseases, and those experiencing side effects related to the ocular surface. Indeed, mild symptoms should not be underestimated, neglected, or denied, because they may very well be the apparent manifestations of more severe, potentially threatening subclinical reactions that may later cause major concerns.

Ic3d Classification of Corneal Dystrophies—edition 2

Purpose: To update the 2008 International Classification of Corneal Dystrophies (IC3D) incorporating new clinical, histopathologic, and genetic information. Methods: The IC3D reviewed worldwide peer-reviewed articles for new information on corneal dystrophies published between 2008 and 2014. Using this information, corneal dystrophy templates and anatomic classification were updated. New clinical, histopathologic, and confocal photographs were added. Results: On the basis of revisiting the cellular origin of corneal dystrophy, a modified anatomic classification is proposed consisting of (1) epithelial and subepithelial dystrophies, (2) epithelial–stromal TGFBI dystrophies, (3) stromal dystrophies, and (4) endothelial dystrophies. Most of the dystrophy templates are updated. The entity “Epithelial recurrent erosion dystrophies” actually includes a number of potentially distinct epithelial dystrophies (Franceschetti corneal dystrophy, Dystrophia Smolandiensis, and Dystrophia Helsinglandica) but must be differentiated from dystrophies such as TGFBI-induced dystrophies, which are also often associated with recurrent epithelial erosions. The chromosome locus of Thiel-Behnke corneal dystrophy is only located on 5q31. The entity previously designated as a variant of Thiel-Behnke corneal dystrophy on chromosome 10q24 may represent a novel corneal dystrophy. Congenital hereditary endothelial dystrophy (CHED, formerly CHED2) is most likely only an autosomal recessive disorder. The so-called autosomal dominant inherited CHED (formerly CHED1) is insufficiently distinct to continue to be considered a unique corneal dystrophy. On review of almost all of the published cases, the description appeared most similar to a type of posterior polymorphous corneal dystrophy linked to the same chromosome 20 locus (PPCD1). Confocal microscopy also has emerged as a helpful tool to reveal in vivo features of several corneal dystrophies that previously required histopathologic examination to definitively diagnose. Conclusions: This revision of the IC3D classification includes an updated anatomic classification of corneal dystrophies more accurately classifying TGFBI dystrophies that affect multiple layers rather than are confined to one corneal layer. Typical histopathologic and confocal images have been added to the corneal dystrophy templates.

The relationship between subbasal nerve morphology and corneal sensation in ocular surface disease.

PURPOSE The purpose of this study was to evaluate the relationship between the in vivo confocal microscopic (IVCM) morphology of subbasal corneal nerves and corneal sensitivity in patients with ocular surface disease. METHODS Ten healthy volunteers (control group), 12 patients with dry eye (dry-eye group), and 14 patients treated with IOP-lowering topical medications (glaucoma group) were included. Central corneal sensation was measured using the contact Cochet-Bonnet esthesiometer. IVCM of the cornea was performed and the following subbasal corneal nerves parameters were analyzed: density, number, width, number of beadings, number of branching, tortuosity, and reflectivity. One eye of each subject was included in the study. RESULTS Corneal sensitivity was significantly decreased in dry-eye and glaucoma patients compared with controls. The density and number of subbasal corneal nerves were also significantly decreased in dry eye and glaucoma patients compared with controls. There was no difference in terms of subbasal nerve width, number of beadings, tortuosity, reflectivity, and number of branching between the dry-eye, the glaucoma, and the control groups. In all subjects, corneal sensitivity correlated positively with the density and number of subbasal nerves; however, in the dry-eye group, corneal sensitivity correlated with the density and the number of nerves, whereas in the glaucoma group, corneal sensitivity correlated only with the tortuosity of subbasal nerves. CONCLUSIONS The relationship between corneal sensation and subbasal nerve morphology, as evaluated with IVCM, depends on the pathophysiological mechanism of ocular surface disease.

Corneal nerve structure and function in patients with non-sjogren dry eye: clinical correlations.

PURPOSE To evaluate the relationship between the in vivo confocal microscopic (IVCM) morphology of subbasal corneal nerves, corneal sensitivity, and clinical parameters in patients with non-Sjögren dry eye disease (NSDD). METHODS Forty-three patients with NSDD and 14 healthy age- and sex-matched control subjects were included. Each patient underwent an evaluation of ocular surface disease symptoms using the Ocular Surface Disease Index (OSDI); tear film break-up time (TBUT); corneal and conjunctival staining (Oxford scale); the Schirmer test; corneal sensation testing using the Cochet-Bonnet esthesiometer; and corneal subbasal nerve analysis with IVCM. One eye of each subject was included in the study. RESULTS Mean corneal sensitivity was significantly lower in the NSDD group as compared with the control group (P = 0.014). Corneal subbasal nerves showed significant changes in NSDD patients as compared with normal subjects: lower density (P < 0.001); increased tortuosity (P < 0.001); number of beadings (P < 0.001); and width (P = 0.041). In patients with NSDD, corneal subbasal nerve density was correlated to age (r = -0.352, P = 0.021); the Oxford scale (r = -0.486, P = 0.01); and central corneal sensitivity (r = 0.383, P = 0.041). The maximum length of nerve fibers within a frame (MaxL) was correlated to the OSDI (r = -0.265, P = 0.019) and the Oxford scale (r = -0.307, P = 0.039). In multivariate analysis after adjustment for age, corneal subbasal nerve density remained correlated to the Oxford score (P < 0.001). The Oxford score was also correlated to central corneal sensitivity (r = -0.304, P = 0.042). CONCLUSIONS NSDD patients have both structural and functional alterations of subbasal corneal nerves and these changes are related to the severity of dry eye.

Ocular Surface Epithelial Thickness Evaluation with Spectral-Domain Optical Coherence Tomography

PURPOSE To use in vivo spectral-domain optical coherence tomography (SD-OCT) to measure corneal, limbal, and bulbar conjunctival epithelial thickness. METHODS A total of 156 eyes of 79 subjects were enrolled in four groups: young control (YC group), < 40 years; middle-aged control (MAC group), > 40 years; patients with dry eye syndrome (KCS group); and patients with glaucoma or ocular hypertension treated with intraocular pressure (IOP)-lowering medication (G group). The central corneal epithelium (CE) thickness, and the limbal (LE) and bulbar conjunctival epithelium (BCE) thickness in four quadrants were measured using SD-OCT. RESULTS The mean thicknesses of the CE, LE, and BCE of the YC group were 48.3 ± 2.9 μm, 83.0 ± 14.3 μm, and 42.0 ± 7.5 μm, and for the MAC group were 48.8 ± 3.0 μm, 84.3 ± 10.1 μm, and 42.2 ± 7.9 μm, respectively. The ocular surface epithelial thickness was not significantly different between the YC and MAC groups. CE thicknesses were not significantly different between the KCS, G, and control groups. The mean LE thicknesses were significantly lower in the KCS and G groups compared with the MAC group. The mean BCE was significantly thicker in the KCS and G groups compared with the MAC group. CONCLUSIONS Anterior segment SD-OCT can provide a noninvasive evaluation of ocular surface epithelial thickness. LE and BCE thickness was modified in dry eye patients and patients using IOP-lowering eye drops, whereas aging seemed to have no effect.

Dry eye disease, dry eye symptoms and depression: the Beijing Eye Study

Aim To investigate the association between dry eye symptoms and depression in an adult population. Methods In this population-based cross-sectional study, a random sample of 1957 subjects from the Beijing Eye Study was examined for dry eye disease (DED) in 2006. All patients completed an interviewer-assisted questionnaire on dry eye symptoms and underwent measurement of tear break-up time (TBUT), slit-lamp evaluation of corneal staining and meibomian gland dysfunction (MGD), and the Schirmer test. In 2011, 1456 subjects from this sample were evaluated for depression using a depression scale. The association between depression symptoms and dry eye clinical tests was evaluated. Results Definite depression was more prevalent in patients with DED than in subjects without DED (13.7±0.4% vs 8.6±0.3%, p=0.02). The depression score was correlated with dry eye symptoms (correlation coefficient r=0.07; p=0.013) but not with TBUT (p=0.18), the Schirmer test (p=0.37), corneal staining (p=0.30) and MGD evaluation (p=0.93). In multivariate regression analysis, the risk of definite depression remained significantly associated with dry eye symptoms (p=0.028) after adjusting for lower cognitive status (p=0.01), rural region of habitation (p=0.023) and lower body weight (p=0.05). Conclusions In an older population from Beijing, depression was associated with DED and in particular with dry eye symptoms.

Comparative Anatomy of Laboratory Animal Corneas with a New-Generation High-Resolution In Vivo Confocal Microscope

Purpose: The aim of the current study was to compare the corneas of three commonly used laboratory animals with a new in vivo confocal microscope. Methods: Six eyes of three adult male New Zealand albino rabbits, six eyes of three adult male Lewis rats, and six eyes of three adult male Swiss mice were used in this study. Corneas were analyzed in vivo using the Rostock Cornea Module of the Heidelberg Retina Tomograph (HRT)-II. For all eyes, 20 confocal microscopic images of each layer, that is, the superficial and basal corneal epithelia, the Bowman layer, the anterior and posterior stroma, and the endothelium, were recorded. The images were then analyzed qualitatively and compared among animals. Cellular densities of anterior and posterior stroma keratocytes of rabbits and endothelium density of the three different animals were also measured and compared. Results: The Rostock Cornea Module of the HRT II was successfully used to analyze all corneal layers of these three commonly used laboratory animals. Although the cellular patterns of the corneal layers of these three animals, as observed with in vivo confocal microscopy, were quite similar, some differences were seen in terms of endothelial cell density and stroma appearance. Superficial cells were seen as hyper- and hyporeflective polygonal cells. Basal cells had dark cytoplasm without visible nuclei and were closely organized. A Bowman layer was observed in all three animals as an amorphous tissue containing fine subepithelial nerve plexus. In rabbits, the stroma consisted of an amorphous ground substance with hyper-reflective structures corresponding with keratocyte nuclei. In rats and mice, numerous reflective stellate structures with no clearly visible nuclei were observed within the stroma. Besides endothelial cell density, the endothelium was similar among the three animals and was seen as hyper-reflective cells with dark limits organized in a honeycomb pattern. Conclusions: The Rostock Cornea Module of the HRT II can provide high-resolution images of all corneal layers of rabbits, rats, and mice without sacrificing animals or preparing tissue. This new device may be useful for evaluating the cornea during experimental animal studies.

Optic Disc Vascularization in Glaucoma: Value of Spectral-Domain Optical Coherence Tomography Angiography

Purpose. To detect changes in optic nerve head (ONH) vascularization in glaucoma patients using spectral-domain OCT angiography (OCT-A). Material and Method. Fifty glaucoma patients and 30 normal subjects were evaluated with OCT-A (AngioVue®, Optovue). The total ONH vessel density and temporal disc vessel density were measured. Clinical data, visual field (VF) parameters, and spectral-domain OCT evaluation (RNFL: retinal nerve fiber layer thickness, GCC: ganglion cell complex thickness, and rim area) were recorded for glaucoma patients. Correlations among total and temporal ONH vessel density and structural and VF parameters were analyzed. Results. In the glaucoma group, total and temporal ONH vessel density were reduced by 24.7% (0.412 versus 0.547; p < 0.0001) and 22.88% (0.364 versus 0.472; p = 0.001), respectively, as compared with the control group. Univariate analysis showed significant correlation between rim area (mm2) and temporal ONH vessel density (r = 0.623; p < 0.0001) and total ONH vessel density (r = 0.609; p < 0.0001). Significant correlations were found between temporal and total ONH vessel density and RNFL, GCC, VF mean deviation, and visual field index. Conclusion. In glaucoma patients OCT-A might detect reduced ONH blood vessel density that is associated with structural and functional glaucomatous damage. OCT-A might become a useful tool for the evaluation of ONH microcirculation changes in glaucoma.

Contribution of In Vivo Confocal Microscopy to the Diagnosis and Management of Infectious Keratitis

Infectious keratitis can lead to irreversible complications and even blindness. Identifying the infectious agent in this condition is a challenge for the ophthalmologist. Corneal cultures are considered to be the gold standard diagnostic tool for this condition. Nevertheless, routine culture and viral investigations may yield positive results in only half the cases. In vivo confocal microscopy (IVCM) is a noninvasive imaging technique that provides high-resolution images of all the corneal layers. Since accurate and rapid diagnosis is important for the management and outcome of infectious keratitis, this disease constitutes one of the most important clinical uses of IVCM. However, in this review, the efficacy of IVCM for infectious keratitis remains inconclusive. Although the value of IVCM has been demonstrated in the diagnosis and management of Acanthamoeba and filamentous fungal keratitis, the current resolution of this imaging technique limits its use in cases of bacterial and viral keratitis. By providing in vivo, repeated, and noninvasive analyses of the cornea, IVCM may also be used to evaluate the effectiveness of treatment and the healing of the cornea in the follow-up of infectious keratitis patients.

In Vivo Confocal Microscopy and Anterior Segment Optical Coherence Tomography Analysis of the Cornea in Nephropathic Cystinosis

OBJECTIVE To analyze the corneas of patients with nephropathic cystinosis using in vivo confocal microscopy (IVCM) and anterior segment optical coherence tomography (AS-OCT). DESIGN Prospective case series. PARTICIPANTS Sixteen eyes of 8 patients with nephropathic cystinosis aged 8 to 21 years. METHODS The ophthalmologic evaluation included best-corrected visual acuity, evaluation of photophobia (0-4), slit-lamp biomicroscopy analysis, intraocular pressure measurement, evaluation of crystal density using a slit-lamp-based scoring of the cornea, as well as AS-OCT and IVCM analysis. MAIN OUTCOME MEASURES The depth of crystal deposition (DCD) in the central cornea and the central cornea thickness (CCT) were assessed using AS-OCT and IVCM. The IVCM images were evaluated for crystal density in each corneal layer and an IVCM score was calculated for each eye. RESULTS All eyes had corneal crystal deposits, with a mean slit-lamp photography score of 2.90+/-0.13 (range, 2.75-3.00). Using AS-OCT, corneal crystals were observed in all eyes. These crystals appeared as hyperreflective punctuate deposits, predominantly observed within the anterior stroma. Measured with AS-OCT, the mean depth of DCD in the central cornea was 291.40+/-81.42 microm (range, 200-531 microm); the mean CCT was 543.47+/-29.62 microm. Using IVCM, the crystals appeared as spindle, needle-shaped, and fusiform hyperreflective bodies measuring from 1 to 175 microm in length and 1 to 30 microm in thickness. Except for the endothelium, randomly oriented crystals were observed in all corneal layers, with the greatest density observed within the anterior stroma. Measured with IVCM, the mean DCD was 426.07+/-88.19 microm (range, 284-531 microm); the mean CCT was 531.87+/-34.77 microm. There was no significant difference between the CCT measurements obtained with IVCM and with AS-OCT (mean difference, 11.31 microm; P = 0.07). Nevertheless, the DCD was significantly higher with IVCM than with AS-OCT (mean difference, 126.25 microm; P<0.0001). CONCLUSIONS In patients with nephropathic cystinosis, IVCM could precisely quantify the density of crystals within the central cornea. Anterior segment OCT and IVCM should be used in further studies evaluating crystal deposition in patients with nephropathic cystinosis. FINANCIAL DISCLOSURE(S) The authors have no proprietary or commercial interest in any materials discussed in this article.