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1.  Topical Interleukin 1 Receptor Antagonist for Treatment of Dry Eye Disease 
JAMA ophthalmology  2013;131(6):715-723.
The immunopathogenic mechanisms of dry eye disease (DED), one of the most common ophthalmic conditions, is incompletely understood. Data from this prospective, double-masked, randomized trial demonstrate that targeting interleukin 1 (IL-1) by topical application of an IL-1 antagonist is efficacious in significantly reducing DED-related patient symptoms and corneal epitheliopathy.
To evaluate the safety and efficacy of treatment with the topical IL-1 receptor antagonist anakinra (Kineret; Amgen Inc) in patients having DED associated with meibomian gland dysfunction.
Design and Setting
Prospective phase 1/2, randomized, double-masked, vehicle-controlled clinical trial.
Seventy-five patients with refractory DED.
Participants were randomized to receive treatment with topical anakinra, 2.5% (n=30), anakinra, 5% (n=15), or vehicle (1% carboxymethylcellulose) (n=30) 3 times daily for 12 weeks.
Main Outcomes and Measures
Primary outcomes were corneal fluorescein staining (CFS), complete bilateral CFS clearance, dry eye–related symptoms as measured by the Ocular Surface Disease Index, tear film breakup time, and meibomian gland secretion quality.
Topical anakinra was well tolerated compared with vehicle, with no reports of serious adverse reactions attributable to the therapy. After 12 weeks of therapy, participants treated with anakinra, 2.5%, achieved a 46% reduction in their mean CFS score (P=.12 compared with vehicle and P<.001 compared with baseline); participants treated with anakinra, 5%, achieved a 17% reduction in their mean CFS score (P=.88 compared with vehicle and P=.33 compared with baseline); and patients treated with vehicle achieved a 19% reduction in their mean CFS score (P=.11). Complete bilateral CFS clearance was noted in 8 of 28 patients (29%) treated with anakinra, 2.5%, vs in 2of 29 patients (7%) treated with vehicle (P=.03). By week 12, treatment with anakinra, 2.5%, and treatment with anakinra, 5%, led to significant reductions in symptoms of 30% and 35%, respectively (P=.02 and P=.01, respectively, compared with vehicle); treatment with vehicle led to a 5% reduction in symptoms.
Conclusions and Relevance
Treatment with topical anakinra, 2.5%, for 12 weeks was safe and significantly reduced symptoms and corneal epitheliopathy in patients with DED. These data suggest that the use of an IL-1 antagonist may have a role as a novel therapeutic option for patients with DED.
PMCID: PMC4167802  PMID: 23599118
2.  Corneal innervation as a window to peripheral neuropathies 
Experimental eye research  2013;113:148-150.
The cornea receives the densest sensory innervation of the body, which is exclusively from small-fiber nociceptive (pain-sensing) neurons. These are similar to those in the skin of the legs, the standard location for neurodiagnostic skin biopsies used to diagnose small-fiber peripheral polyneuropathies. Many cancer chemotherapy agents cause dose-related, therapy-limiting, sensory-predominant polyneuropathy. Because corneal innervation can be detected noninvasively, it is a potential surrogate biomarker for skin biopsy measurements. Therefore, we compared hindpaw-skin and cornea innervation in mice treated with neurotoxic chemotherapy. Paclitaxel (0, 5, 10, or 20mg/kg) was administered to C57/Bl6 mice and peri-mortem cornea and skin biopsies were immunolabeled to reveal and permit quantitation of innervation. Both tissues demonstrated dose-dependent, highly correlated (r = 0.66) nerve fiber damage. These findings suggest that the quantification of corneal nerves may provide a useful surrogate marker for skin peripheral innervation.
PMCID: PMC3737766  PMID: 23769950
Corneal nerves; peripheral neuropathy
3.  Topical Ranibizumab as a Treatment of Corneal Neovascularization 
Cornea  2013;32(7):992-997.
To examine the effect of topical ranibizumab on clinically stable corneal neovascularization (NV).
This was a prospective, open-label, monocentric, uncontrolled, non-comparative study. Ten eyes of 9 patients with corneal NV received topical ranibizumab (1%) 4 times a day for 3 weeks with a follow-up of 16 weeks. The main corneal neovascularization outcome measures were: neovascular area (NA), the area occupied by the corneal neovessels; vessel caliber (VC), the mean diameter of the corneal neovessels; and invasion area (IA), the fraction of the total cornea area covered by the vessels. This study was conducted at the Massachusetts Eye and Ear Infirmary, Boston, MA, USA.
Statistically significant decreases in NA (55.3%, P<0.001), which lasted through 16 weeks, and VC (59%, P<0.001), which continued to improve up to week 16, were observed after treatment. No significant decrease was observed in IA (12.3%, P=0.49). There was no statistically significant change in visual acuity or intraocular pressure. No adverse events ascribed to the treatment were noted.
Topical application of ranibizumab is effective in reducing the severity of corneal NV in the context of established corneal NV, mostly through decrease in VC rather than IA.
PMCID: PMC3920979  PMID: 23407316
corneal neovascularization; VEGF; ranibizumab
4.  Trigeminal stereotactic electrolysis induces dry eye in mice 
Acta ophthalmologica  2012;91(2):e162-e163.
PMCID: PMC3676178  PMID: 22998727
5.  Corneal confocal microscopy reveals trigeminal small sensory fiber neuropathy in amyotrophic lateral sclerosis 
Although subclinical involvement of sensory neurons in amyotrophic lateral sclerosis (ALS) has been previously demonstrated, corneal small fiber sensory neuropathy has not been reported to-date. We examined a group of sporadic ALS patients with corneal confocal microscopy, a recently developed imaging technique allowing in vivo observation of corneal small sensory fibers. Corneal confocal microscopy (CCM) examination revealed a reduction of corneal small fiber sensory nerve number and branching in ALS patients. Quantitative analysis demonstrated an increase in tortuosity and reduction in length and fractal dimension of ALS patients’ corneal nerve fibers compared to age-matched controls. Moreover, bulbar function disability scores were significantly related to measures of corneal nerve fibers anatomical damage. Our study demonstrates for the first time a corneal small fiber sensory neuropathy in ALS patients. This finding further suggests a link between sporadic ALS and facial-onset sensory and motor neuronopathy (FOSMN) syndrome, a rare condition characterized by early sensory symptoms (with trigeminal nerve distribution), followed by wasting and weakness of bulbar and upper limb muscles. In addition, the finding supports a model of neurodegeneration in ALS as a focally advancing process.
PMCID: PMC4199282  PMID: 25360111
motor neuron disease; neuropathy; facial-onset sensory and motor neuronopathy; neuroophthalmology; neuromuscular; cornea; ALS
6.  Short-Term Topical Bevacizumab in the Treatment of Stable Corneal Neovascularization 
American journal of ophthalmology  2012;154(6):940-948.e1.
To evaluate the safety and efficacy of topical bevacizumab in the treatment of corneal neovascularization (NV).
Prospective, non-randomized, interventional case series.
Institutional, multicenter clinical trial.
Study Population
Twenty eyes from 20 patients with stable corneal NV.
Intervention Procedures
Patients were treated with topical 1.0% for 3 weeks and monitored for a total of 24 weeks.
Main Outcome Measures
Primary outcome measures included: neovascular area, defined as the area of the corneal vessels themselves; vessel caliber, defined as the mean corneal vessel diameter; and invasion area, defined as the fraction of the total cornea into which the vessels extended. The occurrence of ocular and systemic adverse events was closely monitored.
As compared to the baseline visit, patients exhibited a statistically significant improvement in neovascular area by week 6 (P = .007) and vessel caliber by week 12 (P = .006). At the final visit, neovascular area, vessel caliber, and invasion area were reduced by 47.5%, 36.2%, and 20%, respectively. The decreases in neovascular area and vessel caliber were statistically significant (P < .001 and P = .003, respectively); however, the reduction in invasion area did not reach statistical significance (P = .06). There were no significant changes in the secondary outcomes and there were no adverse events.
Short-term topical bevacizumab treatment reduced the extent of stable corneal NV as measured by neovascular area and vessel caliber with no associated adverse events. Interestingly, the degree of treatment efficacy was inversely proportional to the baseline invasion area.
PMCID: PMC3498533  PMID: 22967868
7.  In vivo confocal microscopy in goldenhar syndrome: a case report 
BMC Ophthalmology  2013;13:55.
Goldenhar Syndrome is characterized by malformations of multiple anatomical districts. Between these, bulbar dermoids are common and represent a significant clinical problem as they can affect both ocular function and aesthetic comfort.
Histologic characterization of dermoids has been extensively performed; however, no reports exist describing in vivo confocal microscopy (IVCM) of these lesions. We aimed to (i) describe the in vivo confocal morphology of limbal dermoids in Goldenhar syndrome and (ii) compare these findings with standard light microscopy.
Case presentation
A 15-year-old Caucasian female affected by Goldenhar Syndrome showed a left, infero-temporal, limbal neoformation, with extension to the left orbital region. Prior to surgical removal, IVCM was performed with the Heidelberg Retina Tomograph II, Cornea Module, using the “section” modality. The IVCM sections showed structures resembling corneal epithelium and vascular structures. Surgical removal of the lesion was decided as it caused poor eyelid closure. After surgical removal, sectioning and standard optical microscopy were performed. The comparison between IVCM imaging and standard microscopy sections were highly correlated in the detection of the pilar and vascular structures.
This study showed that IVCM may be a useful technique to study limbal dermoids, given its ability to detect typical microscopic features and its comparability to optical microscopy, which is the current standard.
PMCID: PMC3853195  PMID: 24131730
In vivo confocal microscopy; Goldenhar syndrome; Dermoid
8.  Nerves and Neovessels Inhibit Each Other in the Cornea 
To evaluate the regulatory cross-talk of the vascular and neural networks in the cornea.
b-FGF micropellets (80 ng) were implanted in the temporal side of the cornea of healthy C57Bl/6 mice. On day 7, blood vessels (hemangiogenesis) and nerves were observed by immunofluorescence staining of corneal flat mounts. The next group of mice underwent either trigeminal stereotactic electrolysis (TSE), or sham operation, to ablate the ophthalmic branch of the trigeminal nerve. Blood vessel growth was detected by immunohistochemistry for PECAM-1 (CD31) following surgery. In another set of mice following TSE or sham operation, corneas were harvested for ELISA (VEGFR3 and pigment epithelium-derived factor [PEDF]) and for quantitative RT-PCR (VEGFR3, PEDF, and CD45). PEDF, VEGFR3, beta-3 tubulin, CD45, CD11b, and F4/80 expression in the cornea were evaluated using immunostaining.
No nerves were detected in the areas subject to corneal neovascularization, whereas they persisted in the areas that were neovessel-free. Conversely, 7 days after denervation, significant angiogenesis was detected in the cornea, and this was associated with a significant decrease in VEGFR3 (57.5% reduction, P = 0.001) and PEDF protein expression (64% reduction, P < 0.001). Immunostaining also showed reduced expression of VEGFR3 in the corneal epithelial layer. Finally, an inflammatory cell infiltrate, including macrophages, was observed.
Our data suggest that sensory nerves and neovessels inhibit each other in the cornea. When vessel growth is stimulated, nerves disappear and, conversely, denervation induces angiogenesis. This phenomenon, here described in the eye, may have far-reaching implications in understanding angiogenesis.
In this study, we use two different animal models. First, we induce corneal neovascularization and notice that the development of vessels is followed by the disappearance of corneal nerves. Second, we induce loss of corneal nerves, which is followed by the development of neovessels.
PMCID: PMC3562120  PMID: 23307967
9.  Corneal Neovascularization and the Utility of Topical VEGF Inhibition: Ranibizumab (Lucentis) Vs Bevacizumab (Avastin) 
The ocular surface  2012;10(2):67-83.
Corneal avascularity is necessary for the preservation of optimal vision. The cornea maintains a dynamic balance between pro- and antiangiogenic factors that allows it to remain avascular under normal homeostatic conditions; however, corneal avascularity can be compromised by pathologic conditions that negate the cornea’s “angiogenic privilege.” The clinical relevance of corneal neovascularization has long been recognized, but management of this condition has been hindered by a lack of safe and effective therapeutic modalities. Herein, the etiology, epidemiology, pathogenesis, and treatment of corneal neovascularization are reviewed. Additionally, the authors’ recent findings regarding the clinical utility of topical ranibizumab (Lucentis®) and bevacizumab (Avastin®) in the treatment of corneal neovascularization are summarized. These findings clearly indicate that ranibizumab and bevacizumab are safe and effective treatments for corneal neovascularization when appropriate precautions are observed. Although direct comparisons are not conclusive, the results suggest that ranibizumab may be modestly superior to bevacizumab in terms of both onset of action and degree of efficacy. In order to justify the increased cost of ranibizumab, it will be necessary to demonstrate meaningful treatment superiority in a prospective, randomized, head-to-head comparison study.
PMCID: PMC3471139  PMID: 22482468
angiogenesis; bevacizumab; cornea; corneal angiogenic privilege; hemangiogenesis; lymphangiogenesis; neovascularization; ranibizumab; vascular endothelial growth factor; VEGF
10.  Dependence of Corneal Stem/Progenitor Cells on Ocular Surface Innervation 
In a mouse model of denervated cornea, the relationship between corneal progenitor/stem cells and trigeminal innervation was investigated. This study could help understanding corneal diseases when nerve death/dysfunction is known to play a role (e.g. herpetic or diabetic keratopathy).
Neurotrophic keratopathy (NK) is a corneal degeneration associated with corneal nerve dysfunction. It can cause corneal epithelial defects, stromal thinning, and perforation. However, it is not clear if and to which extent epithelial stem cells are affected in NK. The purpose of this study was to identify the relationship between corneolimbal epithelial progenitor/stem cells and sensory nerves using a denervated mouse model of NK.
NK was induced in mice by electrocoagulation of the ophthalmic branch of the trigeminal nerve. The absence of corneal nerves was confirmed with β-III tubulin immunostaining and blink reflex test after 7 days. ATP-binding cassette subfamily G member 2 (ABCG2), p63, and hairy enhancer of split 1 (Hes1) were chosen as corneolimbal stem/progenitor cell markers and assessed in denervated mice versus controls by immunofluorescent microscopy and real-time PCR. In addition, corneolimbal stem/progenitor cells were detected as side population cells using flow cytometry, and colony-forming efficiency assay was performed to assess their function.
ABCG2, p63, and Hes1 immunostaining were significantly decreased in denervated eyes after 7 days. Similarly, the expression levels of ABCG2, p63, K15, Hes1, and N-cadherin transcripts were also significantly decreased in denervated eyes. Stem/progenitor cells measured as side population from NK mice were decreased by approximately 75% compared with normals. In addition, the authors found a significant (P = 0.038) reduction in colony-forming efficiency of stem/progenitor cells harvested from denervated eyes.
Corneolimbal stem/progenitor cells are significantly reduced after depletion of sensory nerves. The data suggest a critical role of innervation in maintaining stem cells and/or the stem cell niche.
PMCID: PMC3317425  PMID: 22232434
11.  In vivo evaluation of DSAEK interface with scanning-laser confocal microscopy 
BMC Ophthalmology  2012;12:32.
Descemet Stripping Automated Endothelial Keratoplasty (DSAEK) allows selective replacement of the endothelium. Post-operative haze and particles can affect the interface quality and, ultimately, visual outcome. In this study, we evaluated DSAEK interface with in vivo laser confocal microscopy (LCM) in order to: (i) correlate interface status with best corrected visual acuity, and (ii) with time from surgery; (iii) correlate interface particle number with best corrected visual acuity. Host-donor interface was imaged and graded using a published reflectivity scale. Particles at the interface were counted.
18 eyes of 16 patients (6 males and 10 females); mean age: 74 ± 8.3 years which underwent DSAEK were examined by means of in vivo laser confocal microscopy between 1 and 24 months after surgery. Host-donor interface was imaged and graded using a published reflectivity scale. Particles present at the interface were counted.
Interface reflectivity was 2.17 ± 1.2 and significantly correlated with visual acuity (Spearman correlation coefficient −0.83; P < 0.001), and with time after surgery (Spearman correlation coefficient −0.87; P < 0.001). Visual acuity was 0.67 ± 0.27. The number of particles was 205 ± 117.8; no correlation was found between this number and visual acuity (Spearman correlation coefficient −0.41; P = 0.15).
DSAEK interface imaged with LCM is helpful in diagnosing poor host-donor interface quality in DSAEK surgery. A good quality interface is related to a better visual acuity. Moreover, the quality of the interface appears to improve as time passes from the surgery. Interface quality is related with visual acuity and improves with time from surgery. LCM should be considered as an added tool in post-DSAEK follow-up of patients. Finally, our study shows that the presence of particles does not influence visual outcome.
PMCID: PMC3441224  PMID: 22853313
DSAEK; Interface; Laser corneal confocal microscopy
12.  Double-Biguanide Therapy for Resistant Acanthamoeba Keratitis 
Case Reports in Ophthalmology  2011;2(3):338-342.
To report the clinical and diagnostic findings of a patient with Acanthamoeba keratitis resistant to both polyhexamethylene biguanide (PHMB)-hexamidine and chlorhexidine-hexamidine treatment.
Slit-lamp biomicroscopy, corneal cell scraping and histopathology were performed on a 39-year-old woman presenting with corneal ulcer in her left eye.
The patient was successfully treated with PHMB-chlorhexidine association therapy. Subsequent perforating keratoplasty remained clear at the last follow-up visit after 7 months and increased visual acuity to 20/20 with correction.
This case emphasizes the proteiform aspects of Acanthamoeba drug resistance, and suggests that PHMB-chlorhexidine association might represent an additional option for cases resistant to standard therapy.
PMCID: PMC3238035  PMID: 22174703
Acanthamoeba keratitis; Biguanide; Diamidine
13.  A Novel Mouse Model for Neurotrophic Keratopathy: Trigeminal Nerve Stereotactic Electrolysis through the Brain 
Neurotrophic keratopathy (NK) is a complex disease affecting millions of people worldwide. The therapy of this disease is still empiric, primarily because of its largely unknown etiopathogenesis. In the present study, the authors developed a novel model of NK that could be helpful for understanding the disease pathogenesis and for testing new therapeutic strategies. They used a highly precise technique, trigeminal stereotactic electrolysis (TSE), to develop this model. Their data demonstrate that the development of disease in mouse, after TSE, greatly resembles that of human NK. In addition, using this model, they studied the role of nerves in corneal cell apoptosis and proliferation.
To develop a mouse model of neurotrophic keratopathy by approaching the trigeminal nerve through the brain and to evaluate changes in corneal cell apoptosis and proliferation.
Six- to 8-week-old male C57BL/6 mice underwent trigeminal stereotactic electrolysis (TSE) to destroy the ophthalmic branch of the trigeminal nerve. Clinical follow-up using biomicroscopy of the cornea was performed at days 2, 4, 5, and 7. To confirm the effectiveness of the procedure, we examined the gross nerve pathology, blink reflex, and immunohistochemistry of the corneal nerves. TUNEL-positive apoptotic and Ki-67–positive proliferating corneal cells were evaluated to detect changes from the contralateral normal eye.
TSE was confirmed by gross histology of the trigeminal nerve and was considered effective if the corneal blink reflex was completely abolished. TSE totally abolished the blink reflex in 70% of mice and significantly reduced it in the remaining 30%. Animals with absent blink reflex were used for subsequent experiments. In these mice, a progressive corneal degeneration developed, with thinning of the corneal epithelium and eventually perforation after 7 days. In all mice, 48 hours after TSE, corneal nerves were not recognizable histologically. Seven days after TSE, an increase in cellular apoptosis in all the corneal layers and a reduction in proliferation in basal epithelial cells were detected consistently in all mice.
TSE was able, in most cases, to induce a disease state that reflected clinical neurotrophic keratitis without damaging the periocular structures. Moreover, corneal denervation led to increased apoptosis and reduced proliferation of epithelial cells, formally implicating intact nerve function in regulating epithelial survival and turnover.
PMCID: PMC3088548  PMID: 21071731

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