Marta Sacchetti

Diagnosis and management of neurotrophic keratitis

Neurotrophic keratitis (NK) is a degenerative disease characterized by corneal sensitivity reduction, spontaneous epithelium breakdown, and impairment of corneal healing. Several causes of NK, including herpetic keratitis, diabetes, and ophthalmic and neurosurgical procedures, share the common mechanism of trigeminal damage. Diagnosis of NK requires accurate investigation of clinical ocular and systemic history, complete eye examination, and assessment of corneal sensitivity. All diagnostic procedures to achieve correct diagnosis and classification of NK, including additional examinations such as in vivo confocal microscopy, are reviewed. NK can be classified according to severity of corneal damage, ie, epithelial alterations (stage 1), persistent epithelial defect (stage 2), and corneal ulcer (stage 3). Management of NK should be based on clinical severity, and aimed at promoting corneal healing and preventing progression of the disease to stromal melting and perforation. Concomitant ocular diseases, such as exposure keratitis, dry eye, and limbal stem cell deficiency, negatively influence the outcome of NK and should be treated. Currently, no specific medical treatment exists, and surgical approaches, such as amniotic membrane transplantation and conjunctival flap, are effective in preserving eye integrity, without ameliorating corneal sensitivity or visual function. This review describes experimental and clinical reports showing several novel and potential therapies for NK, including growth factors and metalloprotease inhibitors, as well as three ongoing Phase II clinical trials.

Alterations of Tear Neuromediators in Dry Eye Disease

OBJECTIVES To evaluate tear levels of neuromediators in patients with dry eye disease and to identify statistical correlations with the clinical findings. METHODS Nineteen patients with dry eye disease (Sjögren syndrome, n = 5 patients; non-Sjögren syndrome, n = 10; and ocular cicatricial pemphigoid, n = 4) and 12 healthy volunteers were enrolled. The eyes of all participants were evaluated by slitlamp examination, Schirmer testing, fluorescein staining, and tear film break-up time. Grading of dry eye severity was recorded. Tear samples were collected, and substance P, calcitonin gene-related peptide (CGRP), neuropeptide Y (NPY), vasoactive intestinal peptide, and nerve growth factor (NGF) concentrations were evaluated by enzyme-linked immunoassay and correlated with the clinical findings. RESULTS Nerve growth factor tear levels were significantly increased in participants with dry eye disease; CGRP and NPY concentrations were significantly decreased when compared with those in healthy participants. Dry eye severity showed a direct correlation with NGF and an inverse correlation with CGRP and NPY tear levels. Nerve growth factor tear levels showed a direct correlation with conjunctival hyperemia and fluorescein staining results, CGRP directly correlated with Schirmer test values, and NPY inversely correlated with tear film break-up time. Subgroup analysis showed that CGRP and NPY but not NGF were changed in autoimmune (ie, Sjögren syndrome and ocular cicatricial pemphigoid) dry eye disease. CONCLUSIONS The decreased tear levels of NPY and CGRP in dry eye disease are related to impaired lacrimal function, and tear levels of NGF are more closely related to corneal epithelial damage. Our findings suggest that NPY, CGRP, and NGF could become useful markers of dry eye severity.

Clinical grading of vernal keratoconjunctivitis

Purpose of reviewThe purpose of the present review is to provide an overview on the clinical features of vernal keratoconjunctivitis on the basis of cases series presented in the literature. Furthermore, a new grading system of vernal keratoconjunctivitis based on the severity of the disease is proposed. Different treatment options are discussed based on the clinical grade of vernal keratoconjunctivitis. Recent findingsRecent epidemiological studies on the demographic, clinical and immunologic features of vernal keratoconjunctivitis are presented. The efficacy and complications of treatments are described. SummaryDiagnosis and treatment of patients is a challenge for ophthalmologists as no precise diagnostic criteria have been established, the pathogenesis is unclear, and antiallergic treatments are often unsuccessful. This review describes old and new concepts of vernal keratoconjunctivitis diagnosis and treatment: the clinical features, the diagnostic criteria, the common features between this and other ocular allergies and the therapeutic strategies. On the basis of this knowledge, a new grading system is introduced based on clinical signs and symptoms of ocular surface inflammation. This new grading of vernal keratoconjunctivitis may help clinicians and researchers to classify disease activity and to establish a common agreement for treatments.

Nerve growth factor therapy for corneal disease

Purpose of review To review the experimental and clinical data on the effects of nerve growth factor (NGF) in corneal physiopathology and to discuss the future development of NGF therapy for corneal diseases. Recent findings NGF plays a key role in the modulation of immune reaction, trophic support, healing of ocular surface, corneal sensitivity and tear film function. These properties of NGF make this neurotrophin a potential therapeutic agent for several corneal diseases. In this review, experimental evidence of the mechanisms of action of NGF on the ocular surface and clinical data on topical NGF use are described and discussed. This review includes the studies performed on corneal diseases such as neurotrophic keratitis, peripheral ulcerative keratopathy, dry eye and corneal surgery. Moreover, experimental studies that extended the NGF action on herpes virus corneal infection and ocular surface stem cell differentiation and proliferation are also reviewed. Summary Since the first clinical use of topical NGF therapy in patients with neurotrophic keratitis, the ocular surface healing and immune-modulating actions of NGF have been extensively studied and demonstrated in the past two decades, opening new perspectives for its use in clinical practice in patients with infective and noninfective diseases of the ocular surface.

Corneal Changes in Neurosurgically Induced Neurotrophic Keratitis

IMPORTANCE Neurotrophic keratitis (NK) represents a sight-threatening complication after trigeminal impairment. To our knowledge, the duration for which trigeminal injury may affect corneal structures and function has not been investigated previously. OBJECTIVE To describe the long-term clinical, morphological, and functional outcomes of NK after neurosurgical trigeminal damage. DESIGN, SETTING, AND PARTICIPANTS Observational case series performed at a corneal and ocular surface diseases referral center in 2010. Eight consecutive patients with monolateral NK from 1 to 19 years after neurosurgery and 20 age- and sex-matched healthy participants were included. MAIN OUTCOMES AND MEASURES Complete eye examination, tear film function tests, corneal staining, and Cochet-Bonnet esthesiometry were performed. The number and density of corneal nerves, number of hyperreflective keratocytes, and corneal epithelial, endothelial, and keratocyte cell densities were evaluated by in vivo slit scanning confocal microscopy. Clinical and morphological data were compared with the contralateral unaffected eyes and with the eyes of healthy control participants. RESULTS All patients showed superficial punctate keratitis and dry eye in the NK eye and a healthy contralateral eye. Decreased corneal sensitivity was observed in all affected eyes (mean [SD], 2.0 [1.9] mm in the affected eyes vs 5.8 [0.3] mm in the contralateral unaffected eyes; P = .01) and was related to decreased subbasal nerve length (P = .04; R = 0.895). Corneal epithelial and endothelial cell densities were significantly decreased and the number of hyperreflective keratocytes was significantly increased in NK eyes compared with contralateral unaffected eyes and with the eyes of healthy participants. A longer duration of NK was associated with lower endothelial cell density (P = .046; R = -0.715). CONCLUSIONS AND RELEVANCE Corneal morphology and function were impaired even years after neurosurgical trigeminal damage, suggesting that assessment of tear film and corneal sensitivity as well as in vivo confocal microscopy examination should be performed in all patients with trigeminal impairment.

Toll-like receptors in ocular surface diseases: overview and new findings

The ocular surface is the first line of defence in the eye against environmental microbes. The ocular innate immune system consists of a combination of anatomical, mechanical and immunological defence mechanisms. TLRs (Toll-like receptors), widely expressed by the ocular surface, are able to recognize microbial pathogens and to trigger the earliest immune response leading to inflammation. Increasing evidence highlights the crucial role of TLRs in regulating innate immune responses during ocular surface infective and non-infective inflammatory conditions. In addition, recent observations have shown that TLRs modulate the adaptive immune response, also playing an important role in ocular autoimmune and allergic diseases. One of the main goals of ocular surface treatment is to control the inflammatory reaction in order to preserve corneal integrity and transparency. Recent experimental evidence has shown that specific modulation of TLR pathways induces an improvement in several ocular inflammatory conditions, such as allergic conjunctivitis, suggesting new therapeutic anti-inflammatory strategies. The purpose of the present review is to summarize the current knowledge of TLRs at the ocular surface and to propose them as potential targets of therapy for ocular inflammatory conditions.

Tailored Approach to the Treatment of Vernal Keratoconjunctivitis

PURPOSE To develop a standardized clinical grading system for the management of patients with vernal keratoconjunctivitis (VKC) and to identify the risk factors associated with a worsened outcome of the disease, including decrease of visual acuity and ocular complications development. DESIGN Retrospective cohort study. PARTICIPANTS A total of 207 consecutive patients with VKC, referred to our Cornea and External Diseases Center from 1997 to 2007, were included in the study. A total of 110 of those patients were included in the follow-up study (range 1-10 years). METHODS Classification and regression tree (CART) analysis was performed to separate the patients into 5 subgroups by therapeutic approach. Regression tree and multivariate logistic regression analyses were performed during follow-up to identify predictors of worse visual outcome. MAIN OUTCOME MEASURES Age, gender, duration and course of disease, signs, symptoms, overall symptoms score, history of atopy, markers of allergy, best-corrected visual acuity, and therapy were collected at baseline and during follow-up. The number of relapses and number of patients with decreased visual acuity were also evaluated in the follow-up. RESULTS A decision tree for VKC treatment was developed by CART analysis, and a new clinical grading system was proposed accordingly. Sixteen patients were classified as grade 0 (absence of symptoms and no therapy); 59 patients were classified as grade 1 (presence of symptoms without photophobia, occasional use of anti-allergic eye drop); 74 patients were classified as grade 2 (presence of symptoms including photophobia, daily anti-allergic treatment); 22 patients with superficial punctuate keratopathy (SPK) were classified as grade 3 (daily anti-allergic treatment associated with occasional topical steroid); and 36 patients were classified as grade 4 (diffuse SPK or corneal ulcer; pulsed high-dose topical steroid). A higher number of relapses and a higher baseline grade of VKC were the main predictor factors for worse visual outcome. CONCLUSIONS This grading system allows for identifying the more severe forms of VKC that are at higher risk of recurrences, corneal ulceration, and worse final visual outcome. FINANCIAL DISCLOSURE(S) The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Upregulation of ICAM-1 expression in the conjunctiva of patients with chronic graft-versus-host disease.

Purpose To correlate conjunctival intercellular adhesion molecule 1 (ICAM-1) expression with cytologic and clinical findings of chronic graft-versus-host disease (GVHD). Methods Seven patients with chronic GVHD-related keratoconjunctivitis and five age-matched normal controls were recruited for the study. Clinical examination included medical history, visual acuity, evaluation of ocular signs and symptoms (scored from 0 to 3), corneal fluorescein staining (scored from 0 to 5 on the basis of the number of corneal sectors involved), Schirmer test type I, and break-up time (BUT). Impression cytology samples were collected from the nasal and inferior bulbar conjunctiva of patients and controls. Goblet cells were counted in three randomly selected fields and averaged. Immunofluorescent staining for ICAM-1 was carried out and the percentage of cells expressing the marker was evaluated. Results All patients showed signs and symptoms of keratoconjunctivitis sicca. Schirmer test type I and BUT were reduced (4.8±6.7 mm/5 min and 3.9±2.7 seconds, respectively). Goblet cells were significantly reduced in GVHD eyes with respect to normal eyes (65±30.5 and 192±16.9 cells/field respectively; p<0.001). Goblet cell number was directly related to Schirmer test values (p<0.01, rho=0.817) and inversely related to total sign score (p<0.01, rho=-0.939). ICAM-1 expression was increased in GVHD eyes with respect to normal controls, in which no staining was observed. ICAM-1 expression showed an inverse relation to goblet cell number (p<0.01, rho=-0.852) and Schirmer test values (p<0.01, rho=-0.926), and was directly correlated to total sign score (p<0.01, rho=0.982). Conclusions Conjunctival ICAM-1 expression is increased in GVHD patients. The severity of the disease is associated with tear parameters, goblet cell decrease, and inflammatory markers, such as ICAM-1.

Demographic and clinical factors associated with development of brimonidine tartrate 0.2%-induced ocular allergy.

Purpose:To identify demographic and clinical characteristics associated with the development of brimonidine tartrate 0.2%-induced ocular allergy. Patients and Methods:In this retrospective study, 133 patients affected by primary open-angle, pigmentary, narrow angle, or pseudo-exfoliative glaucoma and treated with brimonidine tartrate 0.2% were divided into two groups: allergic and non allergic to brimonidine tartrate 0.2%. The distribution of demographic (age and sex), local (history of allergic conjunctivitis, previous eye-drop ocular allergy, use of other concurrent topical medications, amount of topical medications previously used, use of contact lenses, and tear film production), and systemic (history of systemic allergies and use of systemic drugs) factors was evaluated by comparing the brimonidine tartrate 0.2% allergic and the non-allergic groups. Results:In this study, 13.5% of patients (18 of 133) developed brimonidine ocular allergy generally within two weeks from the beginning of treatment (mean time 14.8 ± 17.9 days). The brimonidine tartrate 0.2% allergic group showed a significantly higher frequency of history of ocular allergy to eye-drops (P = 0.048) and to topical beta-blockers (P = 0.019) when compared with the brimonidine tartrate 0.2% non-allergic group. Moreover, the allergic group showed a decreased tear film production (P = 0.044). Conclusion:This study showed that history of eye-drop allergies and reduction of tear film production were more frequently associated with the development of brimonidine tartrate 0.2%-induced ocular allergy.

Clinical applications of NGF in ocular diseases.

Nerve Growth Factor (NGF) and its receptors TrkA and p75 are expressed in physiological states in the anterior and posterior segments of the human eye, where they exert several tissue-specific functions. The roles played by NGF in the homeostasis of the eye and in vision are, therefore, crucial and have been widely investigated both in vitro and in vivo, with growing evidence of an NGF-pathway alteration in several ocular diseases. In this review we describe the functions of NGF in health and diseases states of the eye, and discuss the potential therapeutic effectiveness of NGF in preliminary clinical reports performed in severe ocular diseases unresponsive to any standard treatment. In fact, pharmacodynamic studies showing that NGF administered topically on the ocular surface affects not only the ocular surface but is also able to reach the retina, optic nerve and brain, recently opened new perspectives for the treatment of challenging ocular surface diseases, optic nerve diseases, and degenerative diseases of the retina currently lacking an effective therapy.