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Chiara Fariselli, Giuseppe Giannaccare, Michela Fresina, Piera Versura Ophthalmology Unit, Department of Experimental, Diagnostic and Specialty Medicine, School of Medicine (DIMES), Alma Mater Studiorum University of Bologna and St Orsola-Malpighi Teaching Hospital, Bologna, Italy Aim: To assess the ocular surface parameters, inflammatory marker level in tears, and mucin expression in conjunctival epithelium before and after treatment with trehalose/hyaluronate tear substitute in dry eye (DE) patients.Patients and methods: Fifteen DE patients were evaluated in an open-label, pilot study at enrollment, after 2 days of washout (baseline) and after 1 and 2 months (endpoint) of treatment with a trehalose/hyaluronate tear substitute (one drop/eye/three times daily). Data for symptoms of discomfort (Ocular Surface Disease Index and Visual Analogue Scale pain score), tear film (Schirmer test I, tear film breakup time), ocular surface damage (corneal National Eye Institute) and conjunctival van Bijsterveld scores, impression cytology scored by Nelson’s grade and goblet cells (GCs) number/mm2 analysis, and MUC4 immunostaining, and inflammation (interleukin [IL]-1β, IL-6, and IL-8 levels) were measured.Results: Significant changes at endpoint as compared to baseline were found for Ocular Surface Disease Index score (respectively, mean±SD, 22.2±2.9 vs 38.7±12.7), Visual Analogue Scale score (3.4±1.3 vs 6.6±1.4), tear film breakup time (8.6±1.28 vs 6.17±1.9 seconds), corneal staining (National Eye Institute grade 1.23±0.64 vs 3.37±0.49), conjunctival staining (1.73±1.14 vs 4.17±0.91), impression cytology (Nelson grade 1.10±0.20 vs 1.63±0.54), and GC density (139.9±22.0 vs 107.8±16.2 GC/mm2). IL-1β, IL-6, and IL-8 tear levels showed a significant decrease at endpoint as compared to baseline (respectively, pg/mL tears: 12.3±6.9, 26.6±25.2, 743.5±477.7 vs 33.6±17.3, 112.0±24.3, 1,139.2±671.7).Conclusions: A decrease in ocular discomfort symptoms, surface damage, and tear cytokine levels was shown after 2 months’ treatment with trehalose/hyaluronate tear substitute in DE patients, along with a significant GC density recovery. These results may be associated with the synergic action of both trehalose and hyaluronic acid in targeting different entries of the DE vicious loop. Keywords: dry eye, trehalose, hyaluronic acid, tear substitute, inflammation

Piera Versura, Giuseppe Giannaccare, Marco Pellegrini, Stefano Sebastiani, Emilio C Campos Ophthalmology Unit, Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Alma Mater Studiorum University of Bologna, Sant’Orsola-Malpighi Teaching Hospital, Bologna, Italy Abstract: Neurotrophic keratitis (NK) is a degenerative corneal disease caused by damage of trigeminal corneal innervation, which leads to spontaneous epithelial breakdown and corneal ulceration. The impairment of corneal sensory innervation causes the reduction of both protective reflexes and trophic neuromodulators that are essential for the vitality, metabolism, and wound healing of ocular surface tissues. A wide range of ocular and systemic conditions, including herpetic keratitis, ocular chemical burns, corneal surgery, diabetes, multiple sclerosis, and neurosurgical procedures, can cause NK by damaging trigeminal innervation. Diagnosis of NK requires careful investigation of any ocular and systemic condition associated with the disease, complete ocular surface examination, and quantitative measurement of corneal sensitivity. The clinical stages of NK range from corneal epithelial alterations (stage 1) to persistent epithelial defect (stage 2) and ulcer (stage 3), which may progress to corneal perforation. Management of NK is based on clinical severity, and the aim of the therapy is to halt the progression of corneal damage and promote epithelial healing. Although several medical and surgical treatments have been proposed, no therapies are currently available to restore corneal sensitivity, and thus, NK remains difficult and challenging to treat. The purpose of this review is to summarize available evidence on the pathogenesis, diagnosis, and treatment of NK. Novel medical and surgical therapies including the topical administration of nerve growth factor and corneal neurotization are also described. Keywords: neurotrophic keratitis, neurotrophic corneal ulcer, corneal nerves

Giuseppe Giannaccare, Michela Fresina, Alberto Pazzaglia, Piera Versura Ophthalmology Unit, Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Alma Mater Studiorum University of Bologna, Sant’Orsola‑Malpighi Teaching Hospital, Bologna, Italy Abstract: Graft rejection is the most significant complication corneal transplantation and the leading indication for overall corneal transplantation. Corticosteroid therapy represents the mainstay of graft rejection treatment; however, the optimal route of administration of corticosteroid remains uncertain. We report herein for the first time the multimodal imaging of a case of long-lasting corneal endothelial graft rejection successfully reversed 3 months after dexamethasone intravitreal implant. A 29-year-old Asian female presented with a long-lasting corneal endothelial graft rejection in her left phakic eye. She underwent penetrating keratoplasty for advanced keratoconus 24 months before presentation. Hourly dexamethasone eyedrops, daily intravenous methylprednisolone, and one parabulbar injection of methylprednisolone acetate were administered during the 5 days of hospitalization. However, the clinical picture remained approximately unchanged despite therapy. By mutual agreement, we opted for the off-label injection of dexamethasone 0.7 mg intravitreal implant in order to provide therapeutic concentrations of steroid for a period of ~6 months. No other concomitant therapies were prescribed to the patient. Visual acuity measurement, slit lamp biomicroscopy, anterior segment photography, confocal microscopy, anterior segment optical coherence tomography, laser cell flare meter, intraocular pressure measurement, and ophthalmoscopy were performed monthly for the first postoperative 6 months. Three months after injection, both clinical and subclinical signs of rejection disappeared with a full recovery of visual acuity to 20/30 as before the episode. Currently, at the 12-month follow-up visit, the clinical picture remains stable without any sign of rejection, recurrence, or graft failure. Dexamethasone intravitreal implant seems to be a new potential effective treatment for corneal graft rejection, particularly in case of poor compliance or lack of response to conventional treatment. In addition, it could be especially useful in diabetic patients unable to receive systemic steroids. Keywords: keratoplasty, corneal graft rejection, dexamethasone intravitreal implant, confocal microscopy, keratoconus

Giuseppe Giannaccare,1 Michela Fresina,1 Aldo Vagge,2 Piera Versura1 1Ophthalmology Unit, DIMES, S Orsola-Malpighi Teaching Hospital, University of Bologna, Bologna, Italy; 2Eye Clinic, DiNOGMI, University of Genoa, Genoa, Italy Abstract: This report describes a case of a 72-year-old Caucasian woman presenting with a large neurotrophic keratitis with a large persistent epithelial defect, with a longest linear diameter of 7 mm and greatest perpendicular width of 5 mm, affecting epithelium, Bowman membrane, and anterior stroma. Corneal disease was resistant to conventional treatment and classified as stage 2 according to Mackie classification. Patient was instructed to instill regenerating agent (RGTA) eye drops in the morning, as the first eye drop, once every 5 days in combination with daily cord blood serum (CBS) eye drops 6 times/day. The patient was asked to visit after 1 week (V1), 2 weeks (V2), 3 weeks (V3), and 4 weeks (V4) of study treatment. In V4 treatment, corneal sensitivity improved, and keratitis healed with resolution of stromal inflammation. Global treatment tolerance was very satisfactory. Patient continued the therapy for a further month after complete healing. Currently, the patient has been followed up for 3 months without any sign of keratitis recurrence. To the best of our knowledge, this case report describes for the first time the successful combined use of RGTA and CBS eye drops for the treatment of neurotrophic keratitis resistant to conventional treatment. We hypothesize that RGTA eye drops could provide an optimal migration substrate and that growth factors supplied by CBS eye drops could strengthen the repair process by promoting cell growth over the matrix. Combined RGTA and CBS eye drop therapy could be a new potential option for the successful treatment of resistant neurotrophic keratitis, particularly when each drug alone is not effective. Keywords: neurotrophic keratitis, regenerating agent, cord blood serum eye drops, penetrating keratoplasty, in vivo confocal microscopy

Introduction: Dry eye disease is a multifactorial disease which affects the ocular surface system, and determines ocular discomfort symptoms and visual disturbance. Various types of ocular surgery, including strabismus one, represents a recognized cause for iatrogenic dry eye. However, it is not uncommon that strabismus patients, even not undergone to surgery, report symptoms of ocular discomfort and dryness. Hypothesis We hypothesize that two possible mechanisms may determine dry eye in strabismus patients by setting up a specific vicious circle: firstly, the increased exposure of the area of the bulbar conjunctiva located on the opposite side compared to the deviation may cause the thinning of the tear film lipid layer, with increased tear film instability; secondly, the dysfunctional lubricity secondary to the altered relationship between the eyelids and the deviated globe may cause blinking-related microtrauma, and thus inflammation and tear hyperosmolarity. These two entry points into the vicious circle of dry eye may determine a cascade of detrimental mechanisms, leading to further damage of the tear film, thus closing the disease circle.Discussion: Strabismus patients may be affected by signs and symptoms of dry eye syndrome. The increased exposure of the bulbar conjunctival area along with the dysfunctional lubricity between the eyelids and the deviated eye could be the main underlying pathophysiological mechanisms acting as entry points into the vicious circle of dry eye disease. If our hypothesis was to be confirmed, ocular surface parameters should be routinely investigated in strabismus patients, whilethe use of tear substitutes with the aim of moistening and nourishing the ocular surface could help in reducing dry eye signs and symptoms. [ABSTRACT FROM AUTHOR]