Corneal Complications Related to Dupilumab Use.

OBJECTIVES: The aim of this report is to describe atypical corneal complications associated with dupilumab use. METHODS: This is a series of four cases of adult patients with infiltrative or ulcerative keratitis secondary to dupilumab use. RESULTS: All four patients in this series were prescribed dupilumab for the treatment of atopic dermatitis and developed infiltrative or ulcerative corneal lesions. In all cases, corneal disease was successfully managed with immediate discontinuation of dupilumab and topical steroid treatment. In two cases, the patient also received antibiotic eye drops for infection precautions. CONCLUSIONS: Although dupilumab is most commonly associated with conjunctivitis, physicians should be aware of potential severe corneal complications for early identification and intervention.

Presumed erlotinib-induced bilateral corneal ulcers in a dog with lung tumor.

OBJECTIVE: To report the corneal toxicity of erlotinib in dogs. ANIMAL STUDIED: A 13-year-old castrated male Maltese dog. RESULTS: A dog with lung cancer presented with a month-long history of mucoid discharge and blepharospasm in both eyes. Corneal ulcerations with stromal thinning were diagnosed in both eyes, which were refractory after 2 weeks of treatment with topical antibiotics and artificial tears. The dog was orally administered erlotinib (Tarceva®) by his owner for 2 months to treat his lung cancer. Urgent withholding of erlotinib was recommended, and after 2 weeks of discontinuation, the corneal defects resolved; however, corneal thinning remained until the six-month follow-up. CONCLUSIONS: To the best of author's knowledge, this is the first report in the veterinary literature that describes bilateral corneal ulcers associated with erlotinib administration in a dog.

Peripheral Ulcerative Keratitis in a Young Lady with Systemic Lupus Erythematosus Post Rituximab Infusion-A Case Report.

AIM: We report a new ocular finding of episcleritis (OD) and peripheral ulcerative keratitis (OS) in a 40-year-old lady with a 13-year history of systemic lupus erythematosus (SLE), 3 weeks post-rituximab infusion. MATERIALS & METHODS: Retrospective case report. RESULTS: A 40-year-old lady with a history of SLE and 3 weeks post rituximab infusion developed a new onset episcleritis (OD) and peripheral ulcerative keratitis (OS). As the PUK continued to advance with a leading edge, intravenous methyl prednisolone 1 gm/day was given for 3 days followed by a slow tapering course of oral prednisolone 50 mg/day. Though her ocular inflammation resolved, she developed pneumonia 6 weeks later. At 10 months follow-up, there were no ocular recurrences. She is currently on mycophenolate mofetil 2 gm/day along with oral prednisolone of 10 mg/day. CONCLUSION: This case highlights the new occurrence of episcleritis and PUK in SLE post-rituximab infusion.

Acidic chemical corneal ulceration secondary to nail polish spill in a puppy.

PURPOSE: To describe the treatment of an acidic chemical corneal ulceration in a puppy secondary to nail polish spilling on and adhering to the cornea. CASE SUMMARY: A 12-week-old neutered male Australian Shepherd mix dog was presented to Colorado State University Veterinary Teaching Hospital's (CSU-VTH) Emergency and Urgent Care service acutely after exposure to nail polish spilling on the left eye (OS). Initial ophthalmic examination revealed nail polish adhered to approximately 80% of the cornea with moderate diffuse corneal edema and chemosis, and green nail polish adhered to the skin and fur of the periocular area. Copious flushing with eye wash was performed, but no areas of reduced nail polish adherence were noted. The patient was treated with 1 drop of topical ofloxacin 0.3% ophthalmic solution OS and hospitalized overnight, receiving hyaluronic acid ophthalmic lubrication every hour OS. The treatment plan was carried out for 6 h until time of transfer. In the morning, CSU-VTH's Ophthalmology service removed a nonadhered nail polish plaque in 1 piece using Bishop-Harmon tissue forceps. Following removal, a superficial ulcer secondary to an acidic chemical burn covering 100% of the corneal surface was noted, as well as moderate diffuse corneal edema. Following topical treatment for 8 days, the superficial ulcer healed completely, with no significant long-term consequences. UNIQUE INFORMATION PROVIDED: This is the first report of management of an acidic chemical corneal ulceration secondary to nail polish spill in a puppy. Early assessment and vigilance in treatment was essential for a good prognosis and outcome.

Severe Cocaine-Induced Midline Destructive Lesions (CIMDL) Leading to Orbital Apex Syndrome and Peripheral Ulcerative Keratitis.

PURPOSE: To describe a case of cocaine-induced midline destructive lesions (CIMDL) associated with ocular autoimmune disease.Methods: Observational case report. RESULTS: A 45-year-old man with history of chronic osteolytic sinusitis due to cocaine abuse presented with sudden vision loss in right eye. Ophthalmic examination revealed fixed right mydriasis with extraocular movements limitation and optic disc swelling. Computed tomography showed an orbital infiltrating mass. The diagnosis of orbital-apex syndrome secondary to CIMDL was established. Steroids and antibiotics therapy were started without vision improvement. At 6-months follow-up, a corneal ulcer with characteristics of peripheral ulcerative keratitis (PUK) was evidenced, coinciding with an upper respiratory bacterial infection. CONCLUSIONS: CIMDL and PUK share common pathogenic pathways, with implication of autoimmune factors and exposure to infective antigens. We hypothesized that chronic cocaine use, along with persistent bacterial infection, could have triggered an inflammatory reaction, which contributed to CIMDL development and the appearance of PUK.

Corneal Perforation in Patients Under Treatment With Dupilumab for Atopic Dermatitis.

PURPOSE: We report, for the first time, 2 cases of corneal ulceration and perforation after treatment with dupilumab for atopic dermatitis. METHODS: A 30-year-old woman and a 44-year-old man developed unilateral severe corneal ulceration and perforation while on dupilumab therapy after 3 and 9 months, respectively. RESULTS: Corneal cultures were negative in both cases except for scanty growth of Staphylococcus species on enrichment. Both cases progressed to perforation despite intensive topical antibiotic treatment. The first case required a tectonic keratoplasty to restore globe integrity after failed attempts of corneal gluing and multilayer amniotic membrane transplantation, and the second case was managed successfully with a cyanoacrylate glue patch. CONCLUSIONS: Although there have been previous reports of conjunctival injection and dry eye after dupilumab, these are the first 2 reports of corneal ulceration with rapid progression to perforation in patients under treatment with dupilumab. The underlying pathophysiology for ulcerative keratitis in these cases remains unknown, but there is no doubt that cessation of dupilumab prevented progression of the melting. Severe ocular symptoms while on dupilumab require a prompt discussion with the dermatology team to potentially switch treatment and halt further keratitis progression.

Mechanical behaviour of healthy versus alkali-lesioned corneas by a porcine organ culture model.

BACKGROUND: Cornea is a composite tissue exhibiting nonlinear and time-dependent mechanical properties. Corneal ulcers are one of the main pathologies that affect this tissue, disrupting its structural integrity and leading to impaired functions. In this study, uniaxial tensile and stress-relaxation tests are developed to evaluate stress-strain and time-dependent mechanical behaviour of porcine corneas. RESULTS: The samples are split in two groups: some corneas are analysed in an unaltered state (healthy samples), while others are injured with alkaline solution to create an experimental ulcer (lesioned samples). Furthermore, within each group, corneas are examined in two conditions: few hours after the enucleation (fresh samples) or after 7 days in a specific culture medium for the tissue (cultured samples). Finally, another condition is added: corneas from all the groups undergo or not a cross-linking treatment. In both stress-strain and stress-relaxation tests, a weakening of the tissue is observed due to the imposed conditions (lesion, culture and treatment), represented by a lower stiffness and increased stress-relaxation. CONCLUSIONS: Alkali-induced corneal stromal melting determines changes in the mechanical response that can be related to a damage at microstructural level. The results of the present study represent the basis for the investigation of traditional and innovative corneal therapies.

Allogenic platelet-rich plasma in induced ulcers in rat's cornea / [Plasma rico em plaquetas alogênico em úlceras de córnea induzidas em ratos]

The objective in this study was to evaluate the clinic effect of applying allogenic platelet-rich plasma (PRP) heated or not, for treating cornea ulcers, including the dosage of PDGF-BB in the cornea. The ulcers were induced, standardizing the left eye from 81 rats (Ratus norvegicus, albinus variety), assigned randomly into three groups (N=27): control group (CG) which did not receive any topic treatment; heated PRP group (GA) and PRP group (GP), which received topical treatment every eight hours for five days. Each group underwent evaluation at 24 hours (M1), three days (M3) and five days (M5). The clinical exam evaluated the opacity, vascularization and corneal repair. The corneal PDGF-BB was dosed through the ELISA method. The corneal opacity was decreased in PRP-treated animals (GA and GP) and corneal repair time reduced when compared to CG at M1 and M5. Furthermore, GP showed greater vascularization at M3 compared to M1. Applied allogenic PRP eye drops, heated or not, speed up corneal healing, and reduce corneal repair time. However, the corneal PDGF concentration was not altered in any of the treatments.(AU)

Objetivou-se avaliar o efeito clínico da aplicação de plasma rico em plaquetas alogênico (PRP) aquecido ou não, no tratamento de úlceras de córnea, como a dosagem de PDGF-BB na córnea. As úlceras foram induzidas, padronizando-se o olho esquerdo de 81 ratos (Rattus norvegicus, variedade albinus), aleatoriamente, nos três grupos (N = 27): grupo controle (CG), que não recebeu nenhum tratamento tópico; grupo PRP aquecido (GA) e grupo PRP (GP), que receberam tratamento tópico a cada oito horas, durante cinco dias. Cada grupo foi subdividido em 24 horas (M1), três dias (M3) e cinco dias (M5). O exame clínico avaliou a opacidade, a vascularização e o reparo corneano. O PDGF-BB corneano foi dosado pelo método Elisa. Houve diminuição da opacidade da córnea nos animais tratados com PRP (GA e GP) e diminuição do tempo de reparo da córnea em comparação com CG, M1 e M5. Além disso, foi observada maior vascularização no GP no momento M3 em relação ao M1. A aplicação de colírios de PRP alogênico, aquecidos ou não, acelera a cicatrização da córnea, além de reduzir o tempo de reparo da córnea. No entanto, a concentração de PDGF na córnea não se alterou em nenhum dos tratamentos.(AU)

Bilateral Corneal Perforation in a Patient Under Anti-PD1 Therapy.

ABSTRACT: Immune checkpoint inhibition has improved the clinical outcomes for numerous patients with cancer. However, the downside is a whole new spectrum of immune-related adverse events. We report a 68-year-old man with a history of nonsmall cell lung cancer presenting with a spontaneous corneal perforation in the right eye after 22 cycles of pembrolizumab. In addition, a chronic central nonhealing epithelial defect developed after performing a penetrating keratoplasty. Treatment with autologous serum drops resulted in complete healing of the corneal ulcer, where other conventional therapies had no effect. One month after reinitiating pembrolizumab therapy, our patient presented again with a corneal perforation in the fellow eye. This case describes relapsing sterile ulcerations associated with pembrolizumab use and presents an unexpected cure.

Nivolumab-Induced Ulcerative Keratitis-A Case Report.

PURPOSE: To describe a case of nivolumab-induced ulcerative keratitis rapidly recovering on topical steroid treatment and to determine changes in cytokine levels in the tear fluid caused by nivolumab. METHODS: We report a 34-year-old man receiving nivolumab for metastasized melanoma with severe dry eye symptoms and a persistent corneal epithelial defect. Levels of cytokine and matrix metalloproteinase in tear fluid were measured by multiplex immunoassays. RESULTS: The corneal epithelial defect failed to recover for antiviral and lubrication therapy but resolved within 48 hours after topical steroid therapy was initiated. No recurrence of corneal ulceration was observed with intermittent topical steroid therapy during the remaining period of nivolumab treatment. No Sjögren disease-related autoantibodies were detected in the patient's serum. The levels of inflammatory cytokines and matrix metalloproteinases in the tear fluid were markedly elevated after nivolumab treatment. CONCLUSIONS: Our observations suggest that nivolumab treatment induces a local autoimmune ocular surface disorder resulting in corneal ulceration that promptly resolves using steroid eye drops. The integrity of the corneal epithelial layer can be sustained using intermittent topical steroid therapy in patients receiving nivolumab.

Ethylenediaminetetraacetic Acid Chelation in Herpes Zoster Ophthalmicus Is Associated With a High Rate of Corneal Melt and Perforation.

PURPOSE: To examine the rate and risk factors for band keratopathy after herpes zoster ophthalmicus (HZO) and the outcomes of ethylenediaminetetraacetic acid (EDTA) treatment. METHODS: This is a retrospective review of all subjects with HZO seen at Auckland District Health Board between January 2006 and December 2016. RESULTS: A total of 869 subjects with HZO were included in the study. Median follow-up was 6.3 years (total 5504.4 patient-years). Band keratopathy developed in 13 subjects (1.5%). On multivariate analysis, older age at onset [hazard ratio (HR), 1.092; P = 0.034], intraocular pressure ≥30 mm Hg at presentation (HR, 5.548; P = 0.013), and number of recurrences (HR, 1.849; P < 0.001) were associated with increased risk for band keratopathy. Corneal melt occurred in 22 subjects (2.5%) during the follow-up period. On multivariate analysis, uveitis (HR, 8.618; P = 0.004) and disodium EDTA chelation (HR, 8.666; P < 0.001) were associated with increased risk for corneal melt. EDTA chelation was performed in 8 subjects. Corneal melt occurred after EDTA chelation in 4 subjects, and corneal perforation occurred in 2 subjects. One subject was eviscerated due to severe endophthalmitis after repeated corneal perforation and another required enucleation for recurrent corneal melt and microbial keratitis. CONCLUSIONS: Band keratopathy is an uncommon complication of HZO. Treatment with EDTA chelation might be associated with a significant risk for severe complications in these eyes and should be approached with caution.

Crown Ether Nanovesicles (Crownsomes) Repositioned Phenytoin for Healing of Corneal Ulcers.

Drug repositioning is an important drug development strategy as it saves the time and efforts exerted in drug discovery. Since reepithelization of the cornea is a critical problem, we envisioned that the anticonvulsant phenytoin sodium can promote reepithelization of corneal ulcers as it was repurposed for skin wound healing. Herein, our aim is to develop novel crown ether-based nanovesicles "Crownsomes" of phenytoin sodium for ocular delivery with minimal drug-induced irritation and enhanced efficacy owing to "host-guest" properties of crown ethers. Crownsomes were successfully fabricated using span-60 and 18-crown-6 and their size, morphology, polydispersity index, ζ potential, drug loading efficiency, conductivity, and drug release were characterized. Crownsomes exhibited favorable properties such as formation of spherical nanovesicles of 280 ± 18 nm and -26.10 ± 1.21 mV surface charges. Crownsomes depicted a high entrapment efficiency (77 ± 5%) with enhanced and controlled-release pattern of phenytoin sodium. The optimum crownsomes formulation ameliorated ex vivo corneal drug permeability (1.78-fold than drug suspension) through the corneal calcium extraction ability of 18-crown-6. In vivo study was conducted utilizing an alkali-induced corneal injury rabbit model. Clinical and histopathological examination confirmed that crownsomes exhibited better biocompatibility and minimal irritation due to complex formation and drug shielding. Further, they enhanced corneal healing, indicating their effectiveness as a novel drug delivery system for ocular diseases.

Corneal epithelial injury-induced norepinephrine promotes Pseudomonas aeruginosa keratitis.

Tissue injury causes the secretion of stress hormone catecholamine and increases susceptibility to opportunistic infection. Pseudomonas aeruginosa (P. aeruginosa) is an opportunistic pathogen that is a leading cause of microbial keratitis usually associated with ocular injury or contact lens wear. However, the effect of catecholamine on P. aeruginosa induced corneal infection is unknown. Here, we test if norepinephrine (NE) would promote the progression of P. aeruginosa keratitis in mice. Adult C57BL/6 mouse corneas were scarified and then inoculated with P. aeruginosa. The content of NE was elevated in corneas after scarification and inoculation with P. aeruginosa. Then, exogenous NE was applied to the infected corneas at 24 h after inoculation; control eyes were treated with sterile saline. Topical application of NE aggravated the severity of P. aeruginosa keratitis, accompanied with the increase of clinical score, bacterial load, pathological changes, neutrophils infiltration, bacterial virulence factors and proinflammatory factors levels. In order to further verify the role of NE, N-(2-Chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP-4), a neurotoxin selected to deplete NE, was injected subconjunctivally 12 h before scarification. Pre-depletion of local NE by DSP-4 significantly alleviated the severity of corneal infection. Moreover, NE was also confirmed to increase the bacterial growth and the expression of virulence factors gene in vitro. Together, these data showed that increased corneal NE content facilitated the progression of P. aeruginosa keratitis in mice by amplifying host excessive inflammatory response and bacterial virulence. Therefore, targeting NE may provide a potential strategy for the treatment of P. aeruginosa keratitis.

Systemic Paraquat Intoxication Presenting with Peripheral Ulcerative Keratitis: A Case Report and Literature Review.

PURPOSE: To describe a rare case of systemic paraquat poisoning presenting with peripheral ulcerative keratitis. METHODS: Case report and literature review. RESULTS: Two days after a mouthful of paraquat ingestion, a 48-year-old man presented with painful oral ulcers, abnormal liver functions, and acute kidney injury, followed by the development of crescent-shaped corneal erosions along the limbus and progressive visual impairment in both eyes. Paraquat-induced peripheral ulcerative keratitis was suspected and the patient was treated with intensive topical steroid along with systemic steroid. He recovered completely with good visual outcomes after treatment. CONCLUSIONS: Peripheral ulcerative keratitis is usually an immune-mediated ocular condition, and may be a complication associated with systemic paraquat poisoning. Proper diagnosis and adequate treatment are important for visual recovery.

Late-Onset Sterile Peripheral Ulcerative Keratitis Post-Corneal Collagen Crosslinking.

PURPOSE: To report the incidence, characteristics, clinical presentations, risk factors, and the available treatment modalities of sterile peripheral ulcerative keratitis (PUK) post-corneal collagen crosslinking (CXL). METHODS: This study is a retrospective study including 771 eyes of 474 patients operated for keratoconus or ectasia after LASIK between January 2010 and June 2017 at Beirut Eye & ENT Specialist hospital. The average follow-up period was 4.2 years with a minimum of 1 year post-CXL. RESULTS: Eleven eyes (1.4%) of 8 patients developed late-onset PUK with or without corneal haze and sterile infiltrates. The complications occurred between 3 months and 6 years postoperatively. Their mean age of 39.6 ± 7.1 years was higher than the age of the noncomplicated patients 21.9 ± 8.8 years (P = 0.0001). Four affected patients had inflammatory and autoimmune conditions. Sex, presence of intrastromal ring segments, mean keratometry, and the thinnest pachymetry were found to be insignificantly different between groups, and photorefractive keratectomy was performed more in patients with keratitis. Duration of ultraviolet light exposure was related to sterile ulcerative keratitis development. All patients responded to steroid treatment, and only one had a relapse which resolved with topical cyclosporine 1% drops. CONCLUSIONS: PUK is a rare but serious complication after CXL. Long-term follow-up is necessary to detect late-onset PUK. It is a treatable condition associated with older age and autoimmune conditions but has a good visual outcome.

Bilateral Ulcerative Keratitis Associated With Afatinib Treatment for Non-Small-cell Lung Carcinoma.

PURPOSE: To report a case of afatinib-related bilateral ulcerative keratitis. METHODS: An 85-year-old female patient on treatment with afatinib for non-small-cell lung carcinoma presented with progressive redness, pain, and decreased vision in both eyes. Four weeks before the onset of symptoms, afatinib therapy had been commenced at a dose of 40 mg, once daily. Clinical examination, OCT imaging, photographs, and corneal scrapes were completed at presentation. Afatinib was discontinued. Topical and oral therapy were commenced to treat ulcerative keratitis with close monitoring for signs of progression or corneal perforation. RESULTS: Significant stromal thinning was detected in the inferior cornea of both eyes with an overlying epithelial defect and no infiltrate. No organisms were identified from the corneal scrapes. The patient responded well to treatment, and her vision returned to baseline 4 months after presentation. CONCLUSIONS: To the best of our knowledge, this is the first case in the literature that reports afatinib-related ulcerative keratitis. Careful monitoring for signs of ocular adverse events is recommended during treatment with afatinib for non-small-cell lung carcinoma.