Viral infections and pathogenesis of glaucoma: a comprehensive review.

Glaucoma is a leading cause of irreversible blindness worldwide, caused by the gradual degeneration of retinal ganglion cells and their axons. While glaucoma is primarily considered a genetic and age-related disease, some inflammatory conditions, such as uveitis and viral-induced anterior segment inflammation, cause secondary or uveitic glaucoma. Viruses are predominant ocular pathogens and can impose both acute and chronic pathological insults to the human eye. Many viruses, including herpes simplex virus, varicella-zoster virus, cytomegalovirus, rubella virus, dengue virus, chikungunya virus, Ebola virus, and, more recently, Zika virus (ZIKV) and severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), have been associated with sequela of either primary or secondary glaucoma. Epidemiological and clinical studies suggest the association between these viruses and subsequent glaucoma development. Despite this, the ocular manifestation and sequela of viral infections are not well understood. In fact, the association of viruses with glaucoma is considered relatively uncommon in part due to underreporting and/or lack of long-term follow-up studies. In recent years, literature on the pathological spectrum of emerging viral infections, such as ZIKV and SARS-CoV-2, has strengthened this proposition and renewed research activity in this area. Clinical studies from endemic regions as well as laboratory and preclinical investigations demonstrate a strong link between an infectious trigger and development of glaucomatous pathology. In this article, we review the current understanding of the field with a particular focus on viruses and their association with the pathogenesis of glaucoma.

Possible Association Between Apremilast Therapy and Increased Tearing.

PURPOSE: To evaluate a possible association between apremilast and increased tearing. METHODS: A retrospective observational case series in which reports from VigiBase, the World Health Organization global database of Individual Case Safety Reports, and the literature involving apremilast were evaluated by the National Registry of Drug-Induced Ocular Side Effects for possible increased tearing. RESULTS: A total of 45 cases of possible apremilast-induced increased tearing were identified. All patients were on the standard dose of 30 mg BID. There was no sex difference and ages ranged from 28 to 77 years with an average of 56 years ± 12. Time to onset of the increased tearing ranged from a few days to many months. There were 10 cases of positive dechallenge, 3 cases of positive rechallenge, and 1 case with double-positive rechallenge. In the cases with positive dechallenge and rechallenge, the increased tearing resolved as early as within 2 days after stopping the drug. Most cleared within 2 weeks. One case required 3 months for tearing to return to normal. CONCLUSIONS: Based on patterns and positive dechallenge and rechallenge data, apremilast possibly causes increased tearing on rare occasions.

Atypical Optic Neuritis After Inactivated Influenza Vaccination.

The existence of vaccine-associated optic neuritis is essentially based on the temporal relationship between the administration of a vaccine and the development of optic neuritis in patients with no other known aetiologies for infectious or non-infectious inflammation that could account for the optic neuritis. Influenza vaccine (inactivated or live attenuated) is considered to be one of vaccines that could be related to optic neuritis. The authors describe a rare case of bilateral asymmetric optic neuritis with leptomeningeal enhancement on magnetic resonance imaging (MRI) in a previously healthy young woman who received inactivated influenza vaccination 2 weeks before the onset of symptoms.

Liquid Nitrogen Cryotherapy Treatment of Herpes Simplex Epithelial Keratitis.

A retrospective case series was performed in a university setting for all patients with herpes simplex epithelial keratitis who underwent liquid nitrogen cryotherapy from 2012-2015. Outcome measure was clinical evidence of resolution of epithelial keratitis in the cornea with re-epithelialization. All cases of epithelial keratitis showed partial and complete resolution at day 1 and week 1 respectively. Liquid nitrogen cryotherapy is a safe and effective treatment for herpes epithelial keratitis comparable to other published studies.

Vaccine-Associated Uveitis.

All of the widely administered vaccines have been reported to cause uveitis. The ocular inflammation is usually temporary and resolves with topical ocular steroids. During a 26-year period, a total of 289 cases of vaccine-associated uveitis were reported to three adverse reaction reporting databases. Hepatitis B vaccine, either alone or administered with other vaccines, appears to be the leading offender. Clinicians are encouraged to report cases of vaccine- or drug-associated ocular adverse reactions to www.eyedrugregistry.com.

Conjunctival and corneal ulceration associated with nicorandil.

CONTEXT/OBJECTIVE: To report an association between conjunctival and corneal ulceration and nicorandil therapy for angina. METHODS: Review of the literature and spontaneous reports collected at the National Registry of Drug-Induced Ocular Side Effects (Portland, Oregon), the FDA Spontaneous Reporting System (Bethesda, Maryland) and the World Health Organization's Uppsala Monitoring Center (Uppsala, Sweden). RESULTS: Thirteen case reports of adverse ocular reactions were collected. Abnormal vision (5 reports), corneal ulcer (4 reports) and conjunctival ulcer (4 reports) were associated with nicorandil. Eight subjects were male and 5 female with an average age of 75.4 ± 8.3 years. The average duration of therapy to development of the ADR was 30.4 days ±3 days. Eleven case reports had positive dechallenge and the patients fully recovered. The average dose was 21.6 mg daily. CONCLUSION: Using WHO classification for adverse drug reactions, the association between nicorandil and conjunctival and corneal ulceration is "possible". The case reports indicate that, if recognized, withdrawing nicorandil will lead to resolution of the conjunctival or corneal ulceration. Advanced age and accumulation of nicotinic acid in tissues may be contributory to the risk of developing ocular ulcerations from nicorandil.

Risk of Corneal Graft Rejection and Vaccination: A Matched Case-Control Study From a United States Integrated Health Care System.

PURPOSE: Data on vaccine-associated corneal transplant rejections are limited. We examined the association between graft rejection and vaccination. DESIGN: Matched case-control METHODS: We used electronic health records to identify corneal transplant recipients between January 2008 and August 2022 at Kaiser Permanente Southern California. Cases were transplant recipients who experienced a graft rejection (outcome) during the study period. Randomly selected controls who did not experience a corneal graft rejection at their matched cases' index date (rejection date) were matched in a 3:1 ratio to cases. For controls, index date was determined by adding the number of days between transplant and graft rejection of their matched case to the control's transplant date. RESULTS: The study included 601 cases and 1803 matched controls (mean age 66 years [s.d. 17.0], 52% female, 47% non-Hispanic white). Twenty-three% of cases and 22% of controls received ≥1 vaccinations within 12 weeks prior to the index date. The adjusted odds ratio (aOR) for vaccination in the 12 weeks prior to index date, comparing cases to controls was 1.17 (95% CI: 0.91, 1.50]). The aOR was 1.09 (0.84, 1.43) for 1 vaccination, 1.53 (0.90, 2.61) for 2 vaccinations, and 1.79 (0.55, 5.57) for ≥3 vaccinations. The aOR was 1.60 (0.81, 3.14) for mRNA vaccines, and 1.19 (0.80, 1.78) for adjuvanted/high dose vaccines. CONCLUSIONS: We found no evidence to suggest an association between vaccination and graft rejection. Our findings provide support for the completion of recommended vaccinations for corneal transplant recipients, without significantly increasing the risk of graft rejection.

Trichomegaly and other external eye side effects associated with epidermal growth factor.

CONTEXT/OBJECTIVE: To report an association between epithelial growth factor receptor (EGFR) inhibitors and ocular side effects. MATERIALS AND METHODS: Collection of spontaneous reports at the National Registry of Drug-Induced Ocular Side Effects (Casey Eye Institute, Portland, Oregon) in conjunction with a literature review of EGFR inhibitors associated with ocular adverse drug reactions (ADR). RESULTS: EGFR inhibitors are associated with conjunctivitis, meibomitis, dry eyes, periocular skin changes and trichomegaly. EGFR inhibitors may also cause superficial punctate corneal changes and corneal erosions. DISCUSSION: This is the first overview of all known ocular side effects associated with the use of marketed EGFR inhibitors. This is also the first effort for this class of drugs using the World Health Organization Classification as to causality. CONCLUSION: Ophthalmologists should be aware of possible adverse ocular side effects from EGFR inhibitors and treat based on the type of ADR encountered. All ocular side effects noted are fully reversible upon discontinuation of the drug.

Bilateral uveitis associated with fluoroquinolone therapy.

CONTEXT: Retrospective case series, database study and literature review. Forty case reports are described. OBJECTIVE: To report a possible association between fluoroquinolones and uveitis. MATERIALS AND METHODS: Spontaneous reports from the National Registry of Drug-Induced Ocular Side effects, World Health Organization, and Food and Drug Administration were collected on uveitis associated with systemic fluoroquinolone therapy. A literature review was performed using keywords "uveitis", "fluoroquinolones", and each individual fluoroquinolone name. Additional case reports were collected from the practices of six uveitis subspecialists and one neuro-ophthalmologist. MAIN OUTCOME MEASURES: Data garnered from the reports include the type of fluoroquinolone, age, gender, adverse drug reaction (ADR), dosage, duration of therapy until onset of uveitis, concomitant drugs, systemic disease, dechallenge and rechallenge data. RESULTS: A total of 40 case reports of uveitis associated with fluoroquinolones were identified including 12 men, 27 women, and 1 case in which the gender was not specified. The median age was 54 years. Dosage varied between the different fluoroquinolone drugs, with the median dosage within the range recommended in the package insert for each different fluoroquinolone. Median time from beginning of therapy to appearance of the ADR was 13 days (range 0-20 days). Thirteen patients were 60 years or older, and one patient was taking systemic anti-inflammatory steroids. There were five positive dechallenge case reports. DISCUSSION: According to World Health Organization criteria, the relationship between fluoroquinolone therapy and uveitis is "possible". Causality assessments are based on the time relationship of drug administration, uveitis development, and dechallenge data. CONCLUSIONS: Clinicians should be aware of a possible bilateral fluoroquinolone-associated uveitis, particularly the finding of iris transillumination and pigment dispersion.

Anterior Uveitis following COVID Vaccination: A Summary of Cases from Global Reporting Systems.

PURPOSE: COVID-19 vaccines are currently undergoing long-term safety monitoring, including for ocular side effects. Uveitis following vaccination has been described previously with other vaccines and warrants evaluation for COVID-19 vaccines, especially given their widespread use. CASE REPORTS: We present two cases of patients who developed anterior uveitis following the Moderna COVID-19 vaccine, as reported to the National Registry for Drug-Induced Ocular Side Effects. We also summarize reports of anterior uveitis following COVID-19 vaccination as reported to the World Health Organization global database of individual case safety reports. CONCLUSIONS: Based on the temporal pattern of ocular inflammation following vaccine delivery in these cases, an association may be present between uveitis and COVID-19 vaccination. Further investigation to explore this association is warranted to guide patient care.

Comparison of femtosecond laser-assisted keratoplasty versus conventional penetrating keratoplasty.

PURPOSE: To compare postoperative outcomes for femtosecond laser-assisted keratoplasty (FLAK) with conventional penetrating keratoplasty (PK). DESIGN: Retrospective, comparative surgical series. PARTICIPANTS: Fifty consecutive patients who underwent FLAK and 50 case-controlled patients that had PK at the Casey Eye Institute (Oregon Health & Science University, Portland, OR). METHODS: Data was collected for 50 consecutive cases that underwent zigzag incision FLAK and was compared with 50 subjects that had conventional blade trephine incision PK with similar age, diagnosis and concurrent ocular morbidities over a 2-year follow-up period. MAIN OUTCOME MEASURES: Topographic astigmatism, best spectacle-corrected visual acuity, uncorrected visual acuity, pinhole visual acuity, and the timing of selective suture removal (or adjustment) over various follow-up intervals up to 2 years postoperatively. RESULTS: Significantly lower topographic astigmatism was achieved in the FLAK group over the PK group in the 4- to 6-month follow-up period (P = 0.0324), which correlated well with significant earlier selective suture removal that occurred in that same group over both the 2- to 3-month (P = 0.0025) and 4- to 6-month (P = 0.0236) follow-up periods. This difference in astigmatism was no longer present at any other follow-up period up to 24 months postoperatively. The subset analysis of patients with keratoconus or post-LASIK ectasia did not show any difference in either astigmatism or visual acuity at any time. CONCLUSIONS: Compared with PKP, FLAK had significant improvement in astigmatism before but not after the 6 month postoperative follow-up period. Earlier suture removal was noted in the FLAK group. No significant improvement in best spectacle-corrected visual acuity was noted at any time point. There were no complications or difficulties with trephination in the FLAK procedure across a wide range of corneal pathologies.

Hepatitis B vaccine and uveitis: an emerging hypothesis suggested by review of 32 case reports.

OBJECTIVE: To report a possible association between hepatitis B vaccine and uveitis. METHODS: Spontaneous reports from the National Registry of Drug-Induced Ocular Side Effects, the World Health Organization, and the Food and Drug Administration were collected on hepatitis B vaccine associated with uveitis between 1982 and 2009. In addition, we performed a Medline literature search using the keywords of uveitis, iritis, or vitritis, in combination with vaccines and hepatitis B vaccine. Data garnered from the spontaneous reports included age, gender, adverse drug reaction, temporal association of uveitis with vaccine doses, concomitant drugs, other systemic disease, recovery, and recurrence after repeat dosage. RESULTS: Thirty-two case reports of uveitis occurring after hepatitis B vaccine were reported to the spontaneous reporting databases. The mean age of the patients was 29 years (1-57 years), with 8 male and 24 female patients. The mean number of days until uveitis was reported after vaccination was 3 days (1-15 days). The uveitis was reported to occur after the first vaccination in 15 patients, after the second vaccination in 3 patients, and after the third vaccination in 3 patients; the duration of time to occurrence of uveitis was not reported for 9 patients. One patient had recurrent uveitis after both the second and third doses of vaccine. One patient had recurrent uveitis after the first and second doses of vaccine. CONCLUSION: Hepatitis B vaccine may have a possible association with the development of uveitis in some patients. Immune complex deposition and adjuvant effects are potential pathogenic mechanisms.

Diplopia and fluoroquinolones.

PURPOSE: To report a possible association between fluoroquinolones and diplopia. DESIGN: Database study. PARTICIPANTS: A total of 171 subjects were studied. METHODS: Spontaneous reports from the National Registry of Drug-Induced Ocular Side Effects, World Health Organization, and Food and Drug Administration were collected on fluoroquinolones and diplopia. MAIN OUTCOME MEASURES: Data garnered from the spontaneous reports include the type of fluoroquinolone, age, gender, adverse drug reaction (ADR), dosage, duration of therapy until onset of ADR, concomitant drugs, other systemic disease, and dechallenge and rechallenge data. RESULTS: A total of 171 case reports of diplopia associated with fluoroquinolones were reported, including 76 men, 91 women, and 4 case reports in which the gender was not specified. The median age was 51.6 years. Dosage varied between the different fluoroquinolone drugs, with the median dosage within the range recommended in the package insert for each different fluoroquinolone. Median time from beginning of therapy to appearance of the ADR was 9.6 days (range 1 day to 5 months). Seventeen subjects also had concomitant tendinitis, 49 patients were 60 years or older, 1 patient had renal cysts, and 4 patients were taking systemic anti-inflammatory steroids. There were 53 positive dechallenge and 5 positive rechallenge case reports. CONCLUSIONS: According to World Health Organization criteria, the relationship between fluoroquinolone therapy and diplopia is "possible." This causality assessment is based on the time relationship of drug administration and ADR development, the multiple positive dechallenge and rechallenge reports, and the plausible mechanism by which diplopia could occur: possible tendinitis of the extraocular muscles. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Corrigendum to "The Role of Medications in Causing Dry Eye".

[This corrects the article DOI: 10.1155/2012/285851.].

Oral Anti-Vascular Endothelial Growth Factor Drugs and Ocular Adverse Events.

PURPOSE: To evaluate possible associations between oral anti-vascular endothelial growth factor (VEGF) drugs and ocular side effects. METHODS: Spontaneous reports were collected and evaluated by the National Registry of Drug-Induced Ocular Side Effects on the three oral anti-VEGF drugs (pazopanib, sorafenib, and sunitinib) for possible ocular side effects. RESULTS: Reported side effects include blurred or decreased vision (389 cases); periocular or eyelid edema (273 cases); superficial anterior segment toxicity (270 cases); conjunctival, retinal, or vitreous bleeding (77 cases); retinal detachments (RDs) or retinal tears (RTs) (75 cases); extraocular muscle disorders, including ptosis (51 cases); discoloration of eyelashes (36 cases); retinal arterial or venous occlusions (26 cases); optic nerve disorders, including papilledema and ischemic optic neuropathy (21 cases); uveitis (10 cases); and macular edema (7 cases). Spontaneous reports of possible RD or RT have been associated with pazopanib (31 RDs and 12 RTs), sunitinib (24 RDs and 0 RT), and sorafenib (7 RDs and 2 RTs). CONCLUSIONS: Oral anti-VEGF drugs can cause superficial anterior segment side effects. Pazopanib has been reported to be possibly linked to RDs and RTs. This study suggests that sorafenib and sunitinib are suspected as well. RDs were seldom differentiated into rhegmatogenous retinal detachments (RRDs) or non-RRDs. The association of oral anti-VEGF drugs with RRD and RT are unclassified although this suggests a "signal" requiring further study. The association of oral anti-VEGF drugs with serous retinal detachments, while rare, is plausible. Patients on this class of drugs should be instructed to seek immediate ophthalmic consultation if retinal symptoms occur.

Ocular adverse effects associated with systemic medications : recognition and management.

This article reviews several retrospective case series and reported adverse events regarding common ocular adverse effects related to systemic therapy. It is not intended as a comprehensive summary of these well described adverse drug reactions, nor is it intended to cover the complete spectrum of all ocular adverse effects of systemic therapy. Many systemic drugs may produce ocular toxicity, including bisphosphonates, topiramate, vigabatrin, isotretinoin and other retinoids, amiodarone, ethambutol, chloroquine and hydroxychloroquine, tamoxifen, quetiapine, cyclo-oxygenase (COX)-2 inhibitors, erectile dysfunction agents and some herbal medications. For this review, the certainty of the adverse effect profile of each medication was evaluated according to the WHO Causality Assessment Guide.A certain relationship has been established for pamidronate and alendronate as causes of scleritis, uveitis, conjunctivitis and blurred vision. Topiramate has been established as adversely causing symptoms consistent with acute angle-closure glaucoma, typically bilateral. Vigabatrin has been shown to cause bilateral irreversible visual field defects attributed to underlying medication-induced retinal pathology. Isotretinoin should be considered in the differential diagnosis of any patient with pseudotumour cerebri. Patients taking amiodarone and hydroxychloroquine should be monitored and screened regularly for development of optic neuropathy and maculopathy, respectively. Sildenafil has been reported to cause several changes in visual perception and is a possible, not yet certain, cause of anterior ischaemic optic neuropathy. Patients taking tamoxifen should also be monitored for development of dose-dependent maculopathy and decreased colour vision. COX-2 inhibitors should be included in the differential diagnosis of reversible conjunctivitis. Several herbal medications including canthaxanthine, chamomile, datura, Echinacea purpurea, Ginkgo biloba and liquorice have also been associated with several ocular adverse effects. It is the role of all healthcare professionals to detect, treat and educate the public about adverse reactions to medications as they are an important health problem.

Scientific challenges in postmarketing surveillance of ocular adverse drug reactions.

PURPOSE: To highlight the challenges of postmarketing surveillance for drug-related adverse events in the practice of ophthalmology. DESIGN: A retrospective review of the medical literature and postmarketing surveillance databases. METHODS: MEDLINE literature review of sildenafil-associated or amiodarone-associated optic neuropathy and chloramphenicol-associated blood dyscrasias. RESULTS: Sildenafil, amiodarone, and chloramphenicol may all cause adverse ocular events; however, the data are not conclusive. CONCLUSIONS: Reports in peer-reviewed medical journals may be proven incorrect over time. For drug-induced adverse ocular events, there is little true science after the drug reaches the marketplace, so the percentage of incorrect conclusions may be high. Clinicians should be wary of reports of adverse ocular effects until data are confirmed by multiple authors over the long-term. Even so, spontaneous reports from postmarketing surveillance databases may be the first and only signal of an adverse ocular event.