Insights into mustard gas keratopathy- characterizing corneal layer-specific changes in mice exposed to nitrogen mustard.

Exposure to mustard agents, such as sulfur mustard (SM) and nitrogen mustard (NM), often results in ocular surface damage. This can lead to the emergence of various corneal disorders that are collectively referred to as mustard gas keratopathy (MGK). In this study, we aimed to develop a mouse model of MGK by using ocular NM exposure, and describe the subsequent structural changes analyzed across the different layers of the cornea. A 3 µL solution of 0.25 mg/mL or 5 mg/mL NM was applied to the center of the cornea via a 2-mm filter paper for 5 min. Mice were evaluated prior to and after exposure on days 1, 3, 7, 14, and 28 for 4 weeks using slit lamp examination with fluorescein staining. Anterior segment optical coherence tomography (AS-OCT) and in vivo confocal microscopy (IVCM) tracked changes in the epithelium, stroma, and endothelium of the cornea. Histologic evaluation was used to examine corneal cross-sections collected at the completion of follow-up. Following exposure, mice experienced central corneal epithelial erosion and thinning, accompanied by a decreased number of nerve branches in the subbasal plexus and increased activated keratocytes in the stroma in both dosages. The epithelium was recovered by day 3 in the low dose group, followed by exacerbated punctuate erosions alongside persistent corneal edema that arose and continued onward to four weeks post-exposure. The high dose group showed persistent epitheliopathy throughout the study. The endothelial cell density was reduced, more prominent in the high dose group, early after NM exposure, which persisted until the end of follow-up, along with increased polymegethism and pleomorphism. Microstructural changes in the central cornea at 4 weeks post-exposure included dysmorphic basal epithelial cells and reduced epithelial thickness, and in the limbal cornea included decreased cellular layers. We present a mouse model of MGK using NM that successfully replicates ocular injury caused by SM in humans who have been exposed to mustard gas.

Eyewash with balanced salt solution after intravitreal methotrexate injection in a case of vitreoretinal lymphoma: a simple but effective way to prevent ocular surface toxicity.

Intravitreal methotrexate injection (400 µg/0.1 mL) is the current mainstay for managing vitreoretinal lymphoma. Various complications associated with intravitreal methotrexate are cataract, keratopathy, maculopathy, sterile endophthalmitis, optic atrophy, vitreous haemorrhage, etc. The most common adverse effect of intravitreal methotrexate is keratopathy occurring in more than half of cases. The severity may range from diffuse punctate keratopathy to severe epitheliopathy leading to photophobia, pain, visual blurring, epiphora, etc. This may become a reason for reduced compliance with treatment. The management of these complications includes oral folic acid, topical folinic acid supplementations and reduced frequency or cessation of methotrexate intravitreal injections. Here, we report a simple method of eyewash in a large amount of balanced salt solution after the intravitreal injection procedure to reduce the severity of keratopathy, which helped the patient tolerate the treatment.

Corneal squamous neoplasia: masquerades and management outcomes at a rural eyecare centre.

The authors describe two cases of corneal ocular surface squamous neoplasia (OSSN), presenting at our rural eyecare centre, which were initially misdiagnosed as viral epithelial keratitis and corneal pannus with focal limbal stem cell deficiency. Both the cases were refractory to initial treatment and corneal OSSN was suspected. Anterior segment-optical coherence tomography (AS-OCT) revealed a thickened, hyper-reflective epithelium with abrupt transition and an underlying cleavage plane, features typical of OSSN. Topical 1% 5-fluorouracil (5-FU) therapy was initiated and in two cycles (first case) to three cycles (second case), complete resolution was noted both clinically and on AS-OCT, with no significant side effects. Both patients are currently free of tumour at the 2-month follow-up period. The authors report the rare, atypical presentations of corneal OSSN, discuss the masquerades and highlight the role of primary topical 5-FU in managing corneal OSSN in limited resource settings.

[Chinese expert consensus on the diagnosis and treatment of drug-induced keratopathy (2023)].

Drug-induced keratopathy occurs when the use of certain drugs, particularly ophthalmic preparations, causes pathological changes in the cornea. These changes can be related to the toxic effects of the drugs themselves or drug preservatives. The disease is characterized by a range of clinical features and lacks specific diagnostic criteria, which can lead to misdiagnosis and inappropriate treatment. In order to address these challenges, the Cornea Group of the Ophthalmology Branch of the Chinese Medical Association has brought together leading experts in the field to review key techniques for the diagnosis and treatment of drug-induced keratopathy. As a result, they have developed this consensus to guide the prevention and treatment of this condition.

Mustard Gas-Induced Ocular Surface Disorders: An Update on the Pathogenesis, Clinical Manifestations, and Management.

PURPOSE: Mustard gas (MG) is a potent blistering and alkylating agent that has been used for military and terrorism purposes. Ocular surface injuries are common after exposure to MG. This review provides an update on the pathophysiology, ocular surface complications, and treatment options for MG-related ocular injuries. METHODS: Required information was obtained by reviewing various databases such as Cochrane Library, Google Scholar, and PubMed until March 2022. Data were collected by using keywords: "mustard gas" OR "sulfur mustard" AND "eye" OR "cornea" OR "ocular complication" OR "keratitis" OR "keratopathy" OR "limbal stem cell deficiency" OR "dry eye." RESULTS: Chronic intracellular toxicity, inflammation, and ischemia have been shown to play an essential role in the pathogenesis of MG injury. Ocular surface injuries can have acute, chronic, and most distinctly a delayed-onset presentation leading to various degrees of limbal stem cell deficiency. To date, no treatment has been agreed on as the standard treatment for chronic/delayed-onset MG keratopathy. Based on the authors' experience, we propose a management algorithm for MG-related ocular surface injuries involving optimization of ocular health, anti-inflammatory therapy, and if needed surgical interventions. The management of chronic and delayed-onset presentation remains challenging. CONCLUSIONS: MG keratopathy is a unique form of chemical injury which can lead to a range of ocular surface pathologies. Long-term anti-inflammatory therapy even in patients with seemingly mild disease may potentially reduce the likelihood of the development of more severe delayed-onset disease.

Management of Belantamab Mafodotin-Associated Keratopathy With Rigid Gas-Permeable Corneal Contact Lenses.

ABSTRACT: Belantamab mafodotin is a relatively new drug used in the treatment of relapsed or refractory multiple myeloma. Clinical studies have shown promising responses, but ocular toxicity remains a major challenge with dose reduction or therapy discontinuation being the only available treatment option. We report a clinical case of a patient with severe keratopathy under therapy with belantamab. The use of rigid gas-permeable corneal contact lenses led to a major visual improvement and enabled therapy continuation at full dose over several months. Although this strategy may not be suitable for all patients, it provides an additional option for the treatment of ocular toxicity of this promising agent.

Bilateral toxic epithelial keratopathy following instillation of expired topical eye drops.

WHAT IS KNOWN AND OBJECTIVE: Toxic corneal epitheliopathies are common, but the majority are probably so mild that they are subclinical. Clinically significant epithelial keratopathy can occur following a single drop of topical expired carboxymethylcellulose sodium eye drops. CASE SUMMARY: This case presents A 34-year-old female who presented to the emergency department with a history of severe ocular pain and reduced vision after bilateral instillation of expired eye drops. Both eyes were diagnosed with toxic epithelial keratopathy. The presenting best corrected visual acuity (BCVA) was 20/100 in the right eye and 20/300 in the left eye. The BCVA at last follow-up was 20/20 in both eyes. WHAT IS NEW AND CONCLUSION: The safe use and storage of ophthalmic drugs, including their use before the expiration date, should be reinforced to patients by all healthcare practitioners to avoid complications such as toxic keratopathy.

Limbal stem cell deficiency (LSCD) in rats and mice following whole body exposure to sulfur mustard (SM) vapor.

Ocular injuries following sulfur mustard (SM) exposure are characterized by an acute phase expressed by corneal erosions and inflammation of the anterior segment that after a clinically silent period may be followed by irreversible corneal injuries. The latter includes epithelial defects, chronic inflammation and neovascularization (NV), and were defined in rabbits and in humans as Limbal Stem Cell Deficiency (LSCD), that derived from a delayed loss of corneal epithelial stem cells (ESC), due to secondary processes most likely in the epithelial stem cell (SC) niche. The present study expands our research on SM-induced ocular injury to rodents (rats and mice) following whole body vapor exposure, aiming to define whether the delayed development of LSCD is a general characteristic of SM ocular toxicity. Freely moving rats and mice were exposed to SM vapor (155 µg/l, 10 min). Clinical examination was carried out in rats and included a slit-lamp bio-microscopy, up to 6 months. Eyes were taken for histology at different time points following exposure and evaluation included hematoxylin and eosin (H&E) staining for general morphology, PAS for identification of goblet cells and p63 immunohistochemistry for progenitor epithelial cells. Whole body exposure to SM vapor in rats and mice resulted in acute ocular injury characterized by corneal erosions and ocular inflammation. Following a brief recovery period, 80-90% of the exposed eyes developed corneal NV associated with abnormal corneal epithelium, stromal inflammation and endothelial damage. The late injury was accompanied by migration of conjunctival goblet cells to the cornea and a loss of limbal epithelial progenitor cells, indicating LSCD. The long-term ocular injury shown hereby in rats and mice was consistent with the lesions described in rabbits and in human casualties and demonstrated the general phenomenon of limbal epithelial stem cells deficiency in SM ocular toxicity. The delayed manifestation of this pathology points towards a therapeutic window for the development of medical countermeasures in small animals following exposure in a real life scenario.

Reversible Corneal Decompensation Caused by a Topical Dorzolamide/Timolol Fixed Combination After Descemet Stripping Automated Endothelial Keratoplasty.

PURPOSE: The purpose of this study was to report a case of acute corneal endothelial decompensation caused by a topical dorzolamide/timolol fixed combination (DTFC) after Descemet stripping automated endothelial keratoplasty. METHODS: A 75-year-old woman who was referred to our hospital with a chief complaint of visual disturbance in the right eye after cataract surgery. Anterior segment optical coherence tomography identified an extensive defect in Descemet membrane. The patient subsequently underwent uneventful Descemet stripping automated endothelial keratoplasty surgery for persistent corneal edema. Two weeks after surgery, she had been prescribed topical DTFC twice daily to control elevated intraocular pressure. On the day she started using the eye drops, the patient noticed an acute deterioration of visual acuity. Severe corneal edema was detected at follow-up 5 days later. RESULTS: The topical DTFC was stopped immediately. Thereafter, the corneal edema improved gradually, and there was a reduction in corneal thickness. CONCLUSIONS: Topical DTFC should be used with caution after corneal endothelial transplantation because of the possibility of iatrogenic corneal endothelial dysfunction.

Nicotinamide Riboside Alleviates Corneal and Somatic Hypersensitivity Induced by Paclitaxel in Male Rats.

Purpose: Patients receiving chemotherapy may experience ocular discomfort and dry eye-like symptoms; the latter may be neuropathic in nature. This study assessed corneal and somatic hypersensitivity in male rats treated with paclitaxel and whether it was relieved by nicotinamide riboside (NR). Methods: Corneal sensitivity to tactile and chemical stimulation, basal tear production, and sensitivity of the hindpaw to tactile and cool stimuli were assessed before and after paclitaxel in the absence and presence of sustained treatment with 500 mg/kg per os NR. Corneal nerve density and hindpaw intraepidermal nerve fiber (IENF) density were also examined. Results: Paclitaxel-treated rats developed corneal hypersensitivity to tactile stimuli, enhanced sensitivity to capsaicin but not hyperosmolar saline, and increased basal tear production. Corneal nerve density visualized with anti-ß-tubulin or calcitonin gene-related peptide (CGRP) was unaffected. Paclitaxel induced tactile and cool hypersensitivity of the hindpaw and a loss of nonpeptidergic hindpaw IENFs visualized with anti-protein gene product (PGP) 9.5 and CGRP. NR reversed tactile hypersensitivity of the cornea without suppressing tear production or chemosensitivity; it did not alter corneal afferent density. NR also reversed tactile and cool hypersensitivity of the hindpaw without reversing the loss of hindpaw IENFs. Conclusions: These findings suggest that paclitaxel may be a good translational model for chemotherapy-induced ocular discomfort and that NR may be useful for its relief. The ability of NR to relieve somatic tactile hypersensitivity independent of changes in sensory nerve innervation suggests that reversal of terminal arbor degeneration is not critical to the actions of NR.

Bilateral Marginal Corneal Infiltrates: A Novel Ocular Manifestation of DRESS Syndrome.

BACKGROUND: Drug reaction with eosinophilia and systemic symptoms, known as DRESS syndrome, is a rare drug induced hypersensitivity reaction syndrome. METHODS: case resport. RESULTS: We describe a patient who presented with acute erythematous rash on her face, fever>38ºC, lymphadenopathy, blood abnormalities, and reaction suspected to be amoxicillin clavulanate-related. The patient also had an associated bilateral redness of the conjunctiva, peripheral corneal infiltrates, and anterior chamber with 3+ cells. CONCLUSION: We describe the first occurrence of bilateral marginal corneal infiltrates and acute anterior uveitis associated with amoxicillin clavulanate-induced DRESS syndrome and discuss its pathogenesis.

Corneal Toxicity of Intravitreal Methotrexate Used for the Treatment of Proliferative Vitreoretinopathy in Silicone Oil-Filled Eyes: A Case Series.

PURPOSE: The purpose of this study was to evaluate the corneal toxicity of intravitreal methotrexate used for the prevention of proliferative vitreoretinopathy (PVR). METHODS: In this retrospective case series, eyes with recurrent retinal detachment secondary to PVR were treated with intravitreal injections of 400 µg methotrexate at an average frequency of every 7 days after vitrectomy with silicone oil tamponade. Corneas were examined for corneal epitheliopathy by slit-lamp biomicroscopy before each injection. RESULTS: Thirteen eyes of 12 patients were reviewed. All had a history of recurrent retinal detachment secondary to PVR treated with vitrectomy and silicone oil. The median age was 35 years (range: 9-83). Four patients (33%) were female. The median follow-up duration was 8 weeks (range: 5-10). The median BCVA (logMAR notation) was 2.00 preoperatively, 2.00 at 1 month postoperatively, and 2.00 at the most recent follow-up (P = 0.969). Ten eyes (77%) were pseudophakic. Nine eyes (69%) had a preexisting ocular comorbidity. The median number of injections was 8 (range: 5-10). The median interval time between each injection was 7.0 days (range: 5.8-10.5), and the median follow-up period beyond last injection was 16 weeks (range: 8-28). Two eyes (15.4%) developed mild corneal epitheliopathy during the course of the treatment. CONCLUSIONS: Most eyes in this small series tolerated methotrexate injections without corneal toxicity. In eyes that developed epitheliopathy, the findings were mild and not treatment-limiting.

Corneal Allograft Rejection Associated With Herpes Zoster Recombinant Adjuvanted Vaccine.

PURPOSE: The purpose of this article is to report 3 cases of corneal allograft rejection that occurred in temporal proximity to administration of the zoster subunit vaccine (RZV). METHODS: Three cases of corneal transplant rejection that developed after RZV administration were identified. Clinical history, including existence of other risk factors, timing of rejection, corticosteroid therapy at the time of onset of rejection, and course were reviewed. RESULTS: The onset of symptoms occurred 5 weeks after the first RZV dose in 1 patient and 1 and 6 weeks after the second dose in the other 2 patients. Coexisting risk factors included history of endothelial keratoplasty in the fellow eye in 1 patient and previous failure of a penetrating keratoplasty because of rejection in a second patient. The third patient had a history of 1 episode of rejection in a previous graft that resolved and then experienced graft failure over several years. In 2 patients, rejection developed despite relatively high levels of topical steroid therapy: prednisolone acetate 1%, 4 × per day in 1 patient and difluprednate 0.05%, 3 × per day in a second patient. CONCLUSIONS: RZV, which elicits a more robust immune reaction than the zoster live-attenuated vaccine, ZVL, may increase the risk of allograft rejection in immunocompetent patients with preexisting corneal endothelial or penetrating transplants. Based on the available data, it may be reasonable to increase the topical corticosteroid regimen before the first dose, until approximately 3 months after the second dose of ZVL.

Bilateral ocular deposit of chlorpromazine / Depósito ocular bilateral de clorpromazina

ABSTRACT Chlorpromazine is a medication widely used in psychiatry for the treatment of psychoses, especially schizophrenia. Since 1964, published articles have been correlating this medication with the appearance of ocular alterations. In this paper, we report the case of a 65-year-old patient with ocular effects due to long-term therapy with chlorpromazine. Biomicroscopy of both eyes presented diffuse granular brown deposits, most prominent at the deep stroma and corneal endothelium level. Also showed anterior subcapsular brown deposits with a stellate pattern in the lens. The total amount exceeds 2.000g (significant for the ocular alterations described) considering the patient's daily dosage of chlorpromazine of 300mg for ten years. After performing complete ophthalmic evaluation and discarding other causes for the ocular deposits, we diagnosed a secondary corneal deposit and cataract due to the use of chlorpromazine. This case reinforces the importance of periodic follow-up with an ophthalmologist for chlorpromazine users to trace ocular changes, heeding the exposure time and its dosage.

RESUMO A clorpromazina é uma medicação muito empregada na psiquiatria para tratamento de psicoses, especialmente em casos de esquizofrenia. Desde 1964 existem artigos publicados que correlacionam o uso dessa medicação com o aparecimento de alterações oculares. Neste trabalho, relatamos o caso de um paciente de 65 anos com efeitos oculares devido à terapia de longo prazo com clorpromazina. A biomicroscopia de ambos os olhos apresentou depósitos granulares difusos e de cor marrom, mais proeminente ao nível do estroma profundo e do endotélio da córnea, além de depósitos castanhos subcapsulares anteriores centrais em um padrão estrelado no cristalino. Considerando a dose diária de clorpromazina de 300mg por 10 anos usada pelo paciente, a quantidade total ultrapassa 2.000g (dose considerada significativa para as alterações oculares descritas). Após avaliação oftalmológica completa e descartado outras causas desses depósitos oculares, foram diagnosticados depósito corneano e catarata secundários ao uso de clorpromazina. O caso apresentado reforça a importância do acompanhamento oftalmolÓgico periÓdico de usuários de clorpromazina para o rastreio de alteraçÕes oculares, atentando-se ao tempo de exposição à droga e à posologia da mesma.

Palytoxin-Related Keratoconjunctivitis Assessed by High-Resolution Anterior Segment Optical Coherence Tomography.

Palytoxin (PTX) is produced by corals such as zoanthid corals. Here we present a case of bilateral PTX-induced keratoconjunctivitis. A 63-year-old man presented to the emergency department with symptoms of red eye, purulent discharge, and foreign body sensation in both eyes. On slit lamp examination, epithelial defects in both eyes with a ring-shaped corneal stromal infiltrate in the right eye and a marginal stromal infiltrate in the left eye were noted. High-resolution anterior segment optical coherence tomography (HR-AS-OCT) showed stromal hyperreflectivity and Descemet folds. Bacterial, fungal, and amoebic cultures were taken. Empirical treatment with topical dexamethasone as well as antibiotics and systemic doxycycline was started. The next day the patient stated that he had been handling zoanthid coral without gloves and had rubbed his eyes afterward. Bilateral PTX-induced keratoconjunctivitis was diagnosed. His eyes were irrigated abundantly with saline solution, and umbilical cord serum eye drops were added to the treatment. Treatment was tapered according to improvement of the corneal infiltrates and epithelial defects. After four months, the stromal infiltrates were resolved but corneal scars persisted in both eyes. HR-AS-OCT showed anterior stromal hyperreflectivity corresponding to corneal leucomas. PTX can cause ocular adverse effects such as keratolysis and corneal inflammation, and in some cases can lead to corneal perforation. It can also produce systemic adverse effects, hence the importance of the preventive measures when handling corals that can produce this toxin.

Corneal in vivo confocal microscopy to detect belantamab mafodotin-induced ocular toxicity early and adjust the dose accordingly: a case report.

BACKGROUND: New targeted antibody-drug conjugates (ADCs) against multiple myeloma are known to induce adverse effects that may lead to treatment discontinuation. Preclinical studies reported early severe ocular damage related to the use of belantamab mafodotin (belamaf), including ocular surface inflammation, severe dry eye, and a specific toxicity to the cornea, namely microcystic keratopathy. While belamaf-induced ocular changes have not been prospectively studied, a better understanding of mechanisms involved as well as kinetics may aid in anticipating dose adjustment rather than stopping the treatment once clinical ocular damage is too severe. CASE PRESENTATION: A 61-year-old woman scheduled for belamaf as a fifth-line treatment against multiple myeloma was prospectively included. Clinical examinations were performed before and every 3 weeks afterward, together with in vivo confocal microscopy (IVCM) of the cornea. Visual acuity, symptoms, slit-lamp examination, and ultrastructural changes of the cornea were recorded according to the received dose of belamaf. More precisely, kinetics, shape, density, and location of the toxic corneal lesions have been followed and analyzed using IVCM. Also, specific lesions at the sub-basal nerve plexus layer were detected and characterized for the first time. This advanced approach allowed a better understanding of the belamaf-induced toxicity, further balancing the dose to maintain good vision and eye health while continuing the treatment. CONCLUSIONS: Systematic ultrastructural analysis and follow-up of the corneal state during ADCs treatment for multiple myeloma may open new avenues in the therapeutic approach. Early preclinical detection of ocular damage may accurately contribute to finding the correct dose for each patient and not stopping the treatment due to severe ocular adverse effects.