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Purpose: To evaluate changes in Toll Like Receptors expression at the ocular surface of healthy control volunteers within age. Methods: 51 volunteers were enrolled in a pilot observational study. Clinical (OSDI questionnaire, Schirmer test and BUT) and Biomolecular (ICAM1, Goblet cells) biomarkers were assessed in all subjects. Temporal Conjunctival imprints were used for molecular analysis while nasal ones were harvested for epifluorescence microscopy. Results: Within the age in our sample OSDI score increases, T-BUT values decrease, and goblet cells showed a decreasing trend. Relative real time PCR detected up-regulation of TLR2 and down-regulation of TLR7, TLR8 and MyD88 transcripts. Immunofluorescence data corroborated the PCR results reporting increased TLR2 and decreased TLR7 and TLR8 expression in elder population. A direct correlation was showed between increasing ICAM and increasing TLR2 changes with age. Conclusion: Changes in TLR expression are associated with aging, suggesting physiological role of TLRs in modulating innate and adaptive ocular surface immunity. TLRs age related changes may participate to the failure of ocular surface homeostatic mechanisms with inflammAging.

PURPOSE: Elevated intraocular pressure is a crucial pathologic event for the development of glaucoma (GL). We have reported that nerve growth factor (NGF) reaches retinal cells and the optic nerve (ON) when applied to the eye. Whether ocular application of NGF prevents or reduces damage to retinal ganglion cell (RGC) is not known. METHODS: GL was induced in adult rats by the injection of hypertonic saline into the episcleral vein of the right eye and the left eye used as control. Rats were then treated daily with ocular application of NGF or vehicle solution for 7 weeks. Retinal and ON tissues were then used for structural, immunohistochemical, and biochemical studies. RESULTS: The injection of hypertonic saline into the episcleral vein led to progressive degeneration of RGCs, with the loss of nearly 40% of these cells after 7 weeks of treatment. This cellular loss is associated with the downregulation of NGF and NGF-receptor expression in the retina and ON of the glaucomatous eye and ocular treatment with NGF significantly reduced the deficit induced by GL. CONCLUSIONS: These findings indicate that NGF can exert protective action on RGC degeneration occurring in glaucomatous retina. We suggest that ocular NGF treatment might be a suitable pharmacologic approach to investigate protective mechanisms of degenerating RGCs.

Glaucoma (GL) is an optic neuropathy characterized by progressive loss of visual field due to retinal cell death and optic nerve (ON) degeneration, usually in response to abnormal elevated intraocular pressure (EIOP). It has previously demonstrated that cells of the ON express nerve growth factor (NGF) and NGF-receptors. Relatively little is known, however, about their role on the ON of the glaucomatous eye. The aim of the study was to elucidate this aspect. Using a rat model of GL we investigated the response of NGF and NGF-receptors in the ON of subjects with experimentally induced EIOP. Our results show that EIOP significantly impairs the presence of NGF and NGF-receptor proteins and TrkA gene expression in the ON of glaucomatous eye. These findings suggest that NGF and NGF-receptor might be important signals for the ON response in the EIOP

Nerve growth factor (NGF) is the prototype of the neurotrophin family and promotes the survival of specific populations of neurons, stimulates their morphological differentiation and regulates neuronal gene expression. Since its discovery, NGF attracted clinicians for its potential application in the treatment of neurological disorders. Recent studies demonstrated murine NGF eye drops may be successfully used to treat neurotrophic keratopathy. Neurotrophic keratopathy is a degenerative corneal disease caused by an impairment of the trigeminal nerve, which leads to corneal epithelial defect, ulcer, and perforation. NGF topical application induced complete ulcer healing and a recovery of the corneal sensitivity. The intent of this study is to address the question if murine NGF topical treatment stimulates the production of circulating anti-NGF antibodies. We evaluated patients with neurotrophic keratopathy who underwent topical therapy with NGF eye drops for possible ocular or systemic adverse effects in the course of 16-72 months follow up. None of the patients suffered any adverse reaction, except for mild and transient conjunctival hyperaemia and photophobia. Moreover, none of the treated patients developed circulating antibodies to NGF.

Background: Cataract surgery is the most common operation performed worldwide. A fixed topical corticosteroid-antibiotic combination is usually prescribed in clinical practice for 2 or more weeks to treat post surgical inflammation and prevent infection. However, this protracted schedule may increase the incidence of corticosteroid-related adverse events and notably promote antibiotic resistance. Methods: This International, multicentre, randomized, blinded-assessor, parallel-group clinical study evaluated the non-inferiority of 1-week levofloxacin/dexamethasone eye drops, followed by 1-week dexamethasone alone, vs. 2-week gold-standard tobramycin/dexamethasone (one drop QID for all schedules) to prevent and treat ocular inflammation and prevent infection after uncomplicated cataract surgery. Non-inferiority was defined as the lower limit of the 95% confidence interval (CI) around a treatment difference >–10%. The study randomized 808 patients enrolled in 53 centres (Italy, Germany, Spain and Russia). The primary endpoint was the proportion of patients without anterior chamber inflammation on day 15 defined as the end of treatment. Endophthalmitis was the key secondary endpoint. This study is registered with EudraCT code: 2018-000286-36. Results: After the end of treatment, 95.2% of the patients in the test arm vs. 94.9% of the control arm had no signs of inflammation in the anterior chamber (difference between proportions of patients = 0.028; 95% CI: −0.0275/0.0331). No case of endophthalmitis was reported. No statistically significant difference was evident in any of the other secondary endpoints. Both treatments were well tolerated. Conclusions: Non-inferiority of the new short pharmacological strategy was proven. One week of levofloxacin/dexamethasone prevents infection, ensures complete control of inflammation in almost all patients and may contain antibiotic resistance.

Background/objectives: To compare the number of eye surgical procedures performed in Italy in the 2 months following the beginning of lockdown (study period) because of COVID-19 epidemic with those performed in the two earlier months of the same year (intra-year control) and in the period of 2019 corresponding to the lockdown (inter-year control). Methods: Retrospective analysis of surgical procedures carried out at 39 Academic hospitals. A distinction was made between elective and urgent procedures. Intravitreal injections were also considered. Percentages for all surgical procedures and incidence rate ratios (IRR) for rhegmatogenous retinal detachment (RRD) events were calculated. A p value Results: A total of 20,886 versus 55,259 and 56,640 patients underwent surgery during the lockdown versus intra-and inter-year control periods, respectively. During the lockdown, only 70% of patients for whom an operation/intravitreal injection was recommended, finally underwent surgery; the remaining patients did not attend because afraid of getting infected at the hospital (23%), taking public transportation (6.5%), or unavailable swabs (0.5%). Elective surgeries were reduced by 96.2% and 96.4%, urgent surgeries by 49.7% and 50.2%, and intravitreal injections by 48.5% and 48.6% in the lockdown period in comparison to intra-year and inter-year control periods, respectively. IRRs for RRDs during lockdown dropped significantly in comparison with intra- and inter-year control periods (CI: 0.65–0.80 and 0.61–0.75, respectively, p Conclusion: This study provides a quantitative analysis of the reduction of eye surgical procedures performed in Italy because of the COVID-19 epidemic.

Michele De Maria,1,2 Danilo Iannetta,1 Luca Cimino,3 Marco Coassin,4 Luigi Fontana1 1Ophthalmology Unit, AUSL-IRCCS of Reggio Emilia, Reggio Emilia, Italy; 2Clinical and Experimental Medicine Ph.D. Programme, University of Modena and Reggio Emilia, Modena, Italy; 3Ocular Immunology Unit, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy; 4Ophthalmology, University Campus Bio-Medico of Rome, Rome, ItalyCorrespondence: Luigi FontanaOphthalmology Unit, AUSL-IRCCS of Reggio Emilia, Viale Risorgimento 80, Reggio Emilia 42122, ItalyEmail luifonta@gmail.comAbstract: Cystoid macular edema (CME) is an infrequent, though potentially visually impairing, complication after uneventful cataract surgery. Rupture of the blood-aqueous barrier, with leakage of serum proteins into the aqueous humour, is the main pathogenic factor. However, only a few studies investigated the potential correlation between anterior chamber (AC) inflammation and the risk of cystoid macular changes occurring after surgery. This review aims to identify evidence of a correlation between AC inflammation and the risk of pseudophakic CME. One hundred eighty-seven prospective trials investigating AC inflammation after uncomplicated cataract surgery were identified. Methods of analysis of AC inflammation and the frequency of macular changes were recorded. In the majority (51%) of the studies, inflammation was assessed by clinical grading, followed by laser flare and cell photometry (LFCP) (42%) and aqueous humour sample (4%). Few studies (4%) adopted a combined LFCP and aqueous sample or clinical grading analysis. Sixteen (9%) studies investigated AC inflammation and macular changes by OCT (7%) or fluorescein angiography (2%). Correlation between the amount of postoperative AC inflammation and frequency of CME was documented in 7 studies, not confirmed in 2 studies, and not examined in the other 7. LFCP, more than the other methods of analysis, correlated with the frequency of CME postoperatively. Investigation of the relationship between AC inflammation and the risk of CME changes requires the adoption of quantitative methods of analysis of the inflammatory response after surgery. For this purpose, due to the low level of inflammation in the AC after uncomplicated cataract surgery, LFCP, more than subjective clinical grading, seems a more sensitive and reproducible method of measurement. Inflammation assessment after cataract surgery has a potential role in predicting the risk of CME development and may help to titrate the duration and intensity of treatment in relation to the surgical inflammatory response.Keywords: anterior chamber inflammation, cataract surgery, clinical grading, laser flare photometry, anterior segment optical coherence tomography, aqueous humour sample, cystoid macular edema

This study compared the outcomes of cataract surgery with intraocular lens (IOL) implantation in patients with juvenile idiopathic arthritis (JIA)-associated chronic anterior uveitis treated with antimetabolite drugs and systemic corticosteroids (Non-Biological Group) versus patients treated with antimetabolites and biological drugs (Biological Group). A cohort of patients with cataract in JIA-associated uveitis undergoing phacoemulsification with IOL implantation was retrospectively evaluated. The main outcome was a change in corrected distance visual acuity (CDVA) in the two groups. Ocular and systemic complications were also recorded. The data were collected preoperatively and at 1, 12, and 48 months after surgery. Thirty-two eyes of 24 children were included: 10 eyes in the Non-Biological Group and 22 eyes in the Biological Group. The mean CDVA improved from 1.19 ± 0.72 logMAR preoperatively to 0.98 ± 0.97 logMAR at 48 months (p = 0.45) in the Non-Biological Group and from 1.55 ± 0.91 logMAR preoperatively to 0.57 ± 0.83 logMAR at 48 months (p = 0.001) in the Biological Group. The postoperative complications, including synechiae, cyclitic membrane, IOL explantation, glaucoma, and macular edema, were not statistically different between the two groups. An immunosuppressive treatment with biological drugs can improve the visual outcome after cataract surgery in patients with JIA-associated uveitis, but it does not significantly reduce postoperative ocular complications.

Purpose Overtreatment with topical ophthalmic preparations can lead to toxic corneal ulcer development. This study aimed to investigate the clinical and visual impact of toxic corneal ulcers and the management and risk factors for their development and outcomes. Methods Clinical records of 226 consecutive patients with corneal ulcers referred to our tertiary care center were retrospectively evaluated. Frequency, clinical features, and management of toxic corneal ulcers are described. The relationship between clinical severity and outcomes (healing time, corneal transparency, and visual acuity) of toxic corneal ulcers and the number and classes of topical drugs, the number of daily instillations, and the duration of treatment were statistically evaluated. Results Toxic corneal ulcer was diagnosed in 9% (21/226) of all patients. After topical treatment discontinuation, the cornea spontaneously healed in all patients in 2 to 21 days. A longer healing time was related to a greater number of topical drugs used (p=0.029), a greater frequency of daily instillations (p=0.042), and a longer duration of treatment (p=0.048). The specific drugs used did not significantly influence healing time. After resolution, 16 out of 21 patients showed corneal scarring and impairment of visual function. The severity of corneal haze was related to the number of drugs used (p=0.023), to the frequency of daily instillations (p=0.031), and to the healing time (p=0.008). Conclusions Toxic corneal ulcer is a frequent disease that can potentially lead to permanent visual impairment. A high-dose regimen is the major risk factor for corneal toxic ulcer development and poor visual outcomes.

http://hdl.handle.net/20.500.11768/97003 Bckground In vitro and in vivo studies demonstrated the antiviral efficacy of nerve growth factor (NGF) and its cyto-protective effect in herpes simplex virus (HSV)-infected cells. The aims of this study were to evaluate the role of endogenous NGF in HSV corneal infection, and the effects of topical NGF treatment on herpetic keratitis. Methods Herpetic keratitis was induced in 40 rabbits with the HSV-1 McKrae strain. Animals were divided into four groups, and treated with topical neutralizing anti-NGF antibodies, NGF, acyclovir or balanced salt solution (BSS) respectively. The clinical course of HSV keratitis was evaluated and scored by slit-lamp examination. In addition, biochemical (immunohistochemistry for glycoprotein D) and molecular (nested PCR for glycoprotein D) analyses were carried out to estimate viral replication. Results Treatment with anti-NGF antibodies induced a more severe keratitis associated with increased biochemical and molecular markers of active viral replication. Two animals in this group developed lethal HSV encephalitis. Conversely, topical treatment with NGF induced a significant amelioration of clinical and laboratory parameters when compared to the BSS treated group (control). No significant differences were observed between NGF- and acyclovir-treated groups. Conclusions This study demonstrated the crucial role of endogenous NGF in herpetic keratitis. The comparable effects of NGF and acyclovir confirm the antiviral activity of NGF, and indicate a potential use of topical NGF in herpetic keratitis.

Keratoconus is the most common corneal dystrophy that leads to severe visual impairment. Although the major etiological factors are genetic, the pathogenetic mechanism(s) is unknown. No medical treatments exist, and the only therapeutic approach is corneal transplantation. Recent data demonstrate the involvement of nerve growth factor (NGF) in trophism and corneal wound healing. In this study, we investigated alterations in the NGF pathway in keratoconus-affected corneas and found a total absence of the NGF-receptor TrkA (TrkA NGFR ) expression and a decreased expression of NGF and p75 NTR . The absence of TrkA NGFR expression was associated with a strong increase in the Sp3 repressor short isoform(s) and a lack of the Sp3 activator long isoform. Sp3 is a bifunctional transcription factor that has been reported to stimulate or repress the transcription of numerous genes. Indeed, we found that Sp3 short isoform(s) overexpression in cell culture results in a down-regulation of TrkA NGFR expression. We suggest that an imbalance in Sp transcription-factor isoforms may play a role in controlling the NGF signaling, thus contributing to the pathogenesis of keratoconus. This mechanism for the transcriptional repression of the TrkA NGFR gene can provide the platform for the development of a therapeutic strategy.

OBJECTIVE: To evaluate the effects on signs and symptoms of a coexisting vernal keratoconjunctivitis in patients treated with oral montelukast sodium for asthma. METHODS: Twelve patients with vernal keratoconjunctivitis and asthma were enrolled in this pilot study. Topical eyedrops or any systemic treatment was discontinued for at least 7 days before montelukast treatment. Patients were asked to grade their ocular discomfort daily. The following signs and symptoms were also recorded and graded through medical examination at baseline,after 15 days of treatment, and 15 days after treatment discontinuation: physician-evaluated tarsal and bulbar papillae, hyperemia, secretion, and chemosis; and patient-evaluated itching, burning, tearing, photophobia, foreign body sensation, secretion, and redness. Peak expiratory flow rate at 8 AM was also recorded. Samples were collected at the same time points for enzyme-linked immunosorbent assay measurement of leukotriene B4 in tears and leukotriene E4 in urine. RESULTS: Eight of the 10 patients evaluated reported a reduction in symptoms at the end of treatment. Montelukast treatment significantly decreased physician-rated hyperemia, secretion, and chemosis as well as patient-rated burning, tearing, photophobia, secretion, and redness. Effects persisted 15 days after discontinuation of treatment. Clinical changes were associated with a significant increase in leukotriene B4 in tears and a significant decrease in leukotriene E4 in urine after 15 days of treatment. CONCLUSION: The significant and persistent reduction of ocular signs and symptoms in asthmatic patients with vernal keratoconjunctivitis treated for 15 days with montelukast strongly suggests the need for double-masked placebo-controlled trials to confirm the potential of this new treatment in vernal keratoconjunctivitis.