Ophthalmic Immune-Related Adverse Events and Association with Survival: Results from a Real-World Database.

PURPOSE: Assessing immune-related ocular toxicities from immune checkpoint inhibitors (ICIs) is crucial, though rare. This study, utilizing real-world data, examines the occurrence of ophthalmic immune-related adverse events (irAEs) after ICI treatment and their impact on overall survival. DESIGN: A retrospective cohort study METHODS: Data were obtained from TriNetX, an aggregated electronic health records database. Patients who developed ophthalmic irAEs within 1 year after the first instance of ICI therapy were included. Participants with defined ocular toxicities 6 months before ICI treatment were excluded. Subjects were paired with controls using propensity scores derived from demographics and cancer type. A Cox proportional hazard model was used to determine hazard ratios. A Kaplan-Meier survival function was evaluated with the log-rank test based on the development of ophthalmic irAEs in a 12-month landmark analysis. RESULTS: A cohort of 41,020 patients comprising 57.4% males with a mean age of 65.2±11.9 years was included. The five most prevalent ophthalmic irAEs in this cohort were dry eye syndrome (2%), conjunctivitis (0.87%), blepharitis (0.51%), anterior uveitis (0.39%), and keratitis (0.38%). Dry eye syndrome was the most common irAE among all ICI classes. Subjects taking CTLA-4 inhibitor plus PD-1 inhibitor and CTLA-4 inhibitors had higher rates of anterior uveitis (1.39% and 1.29%, respectively) than PD-1 inhibitors (0.27%) and PD-L1 inhibitors (0.14%) within 1 year after taking ICI. After a 12-month landmark analysis, there was a significant decreased chance of survival for the following categories: any ophthalmic irAE (HR, 1.37; 95% CI, 1.20-1.56; P < 0.0001), neuro-ophthalmic irAE (HR, 1.53; 95% CI, 1.09-2.14; P = 0.0124), and cornea and ocular surface irAE (HR, 1.34; 95% CI, 1.15-1.56; P < 0.0001). CONCLUSIONS: Ophthalmic irAEs involving the anterior segment are more frequent than the posterior segment, regardless of ICI class. Ophthalmic irAEs may also portend decreased survival. This insight could help guide clinicians aggressively manage irAEs and allow patients to continue ICI therapy despite having ocular issues.

Reduction of Teprotumumab-Induced Hearing Loss With Comparable Efficacy Using Half-Dose Therapy.

Teprotumumab has been shown to be effective in the treatment of thyroid eye disease, a potentially vision-threatening condition. Adverse events, including sensorineural hearing loss, have been associated with teprotumumab. The authors present the case of a 64-year-old female who discontinued teprotumumab due to significant sensorineural hearing loss after 4 infusions, along with other adverse events. The patient was unresponsive to a subsequent course of intravenous methylprednisolone and orbital radiation, during which she experienced worsening thyroid eye disease symptoms. Teprotumumab was restarted 1 year later, at a half dose of 10 mg/kg for 8 infusions. Three months post-treatment, she retains resolution of double vision and orbital inflammatory signs, and significant improvement in proptosis. She tolerated all infusions with an overall reduction in the severity of her adverse events and without return of significant sensorineural hearing loss. The authors conclude that a lower dose of teprotumumab can be effective for patients with active moderate-severe thyroid eye disease who experience significant or intolerable adverse events.

Teprotumumab-Related Hyperglycemia.

CONTEXT: Graves orbitopathy (GO) or thyroid eye disease is a potentially sight-threatening and disfiguring autoimmune disease. Teprotumumab is a monoclonal antibody against the insulin-like growth factor-I receptor that was recently approved for GO treatment. Hyperglycemia is a recognized adverse event of teprotumumab, occurring in 10% of patients in 2 recent randomized controlled trials. OBJECTIVE: Our study aimed to report the incidence, severity, management, and longitudinal glycemic changes in patients treated with teprotumumab in an academic practice cohort. METHODS: This longitudinal, observational study included all consecutive patients treated with teprotumumab between March 2020 and May 2022 at 1 institution. Hemoglobin A1c (HbA1c) was measured every 3 months. RESULTS: Forty-two patients with baseline normoglycemia (n = 22), prediabetes (n = 10), and diabetes (n = 10) were followed for a mean of 47.5 weeks. Overall, HbA1c increased by 0.5% at 3 months. Least-squares mean changes in HbA1c at 3 months were 1.3 (P < .001), 0.7 (P = .01), and 0.1 (P = .41) in patients with diabetes, prediabetes, and normoglycemia, respectively. Twenty-two patients (52%) had hyperglycemia, which was graded as mild, moderate, and life-threatening in 55% (12/22), 41% (9/22), and 5% (1/22) of cases, respectively. Age, pre-existing diabetes, and Hispanic and Asian race/ethnicity were significant risk factors for hyperglycemia. Among patients with hyperglycemia, 36.4% (8/22) returned to baseline glycemic status at last follow-up. CONCLUSION: While effective, teprotumumab carries a significant risk of hyperglycemia, especially in patients with diabetes. Hyperglycemia may persist after stopping teprotumumab. These findings underscore the importance of guidelines for screening and management of teprotumumab-related hyperglycemia.

New Onset or Deterioration of Thyroid Eye Disease After mRNA SARS-CoV-2 Vaccines: Report of 2 Cases and Literature Review.

CONTEXT: Occurrence of Graves' disease (GD) has been reported following SARS-CoV-2 vaccine administration, but little is known about thyroid eye disease (TED) after SARS-CoV-2 vaccination. OBJECTIVE: We describe 2 cases of TED activation following mRNA SARS-CoV-2 vaccination and review additional cases reported in the literature. METHODS: We report 2 cases of TED activation following SARS-CoV-2 vaccination: 1 case of TED worsening in a patient with GD, and 1 of de novo active TED progressing to dysthyroid optic neuropathy in a patient with a history of Hashimoto hypothyroidism. Our literature search revealed 8 additional reported TED cases associated with SARS-CoV-2 vaccination until June 2022. We review the characteristics, duration, and management of TED following SARS-CoV-2 vaccination in these cases. RESULTS: Of all 10 reported TED cases following SARS-CoV-2 vaccination, 4 developed new-onset TED and 6 previously stable TED cases experienced significant deterioration. Six patients had known GD and 2 patients had Hashimoto thyroiditis. Two cases progressed to dysthyroid optic neuropathy, 6 had moderate/severe active disease, and 2 had mild disease that did not require treatment. Seven TED cases received teprotumumab and had a favorable response, 2 of whom had prior limited response to initial prednisone or methylprednisolone and tocilizumab therapy. CONCLUSION: New diagnosis or deterioration of TED after mRNA SARS-CoV-2 vaccination can occur, with most cases described in patients with underlying autoimmune thyroid disease. Our report raises awareness to this potential complication to promote early recognition and prompt management of TED associated with mRNA SARS-CoV-2 vaccines. Further studies are needed to explore the mechanism, risk factors, prevention, and treatment of TED following mRNA SARS-CoV-2 vaccination.

Teprotumumab and the Evolving Therapeutic Landscape in Thyroid Eye Disease.

CONTEXT: Thyroid eye disease (TED) is a sight-threatening and debilitating autoimmune condition, with limited therapies available, that often poses diagnostic and therapeutic challenges. In recent years, the treatment landscape has shifted to early intervention with targeted therapy. METHODS: A PubMed review of the literature was conducted for the period between 1979 and 2021. Search terms included thyroid eye disease, teprotumumab, targeted therapy, Graves disease, Graves ophthalmopathy, dysthyroid optic neuropathy, and related terms in different combinations. Novel biologic therapies for TED have emerged as alternatives to traditional steroid regimens in recent years. New insights into TED pathophysiology have uncovered the role of the insulin-like growth factor 1 receptor (IGF-1R) and led to the development of teprotumumab, an IGF-1R-inhibiting monoclonal antibody. RESULTS: Randomized clinical trials demonstrating the efficacy of teprotumumab for TED led to Food and Drug Administration approval. Teprotumumab is gradually replacing immunosuppressive agents as first-line therapy in the United States for active moderate-to-severe TED, while emerging reports also show its use in other stages of the disease. Recent data highlight risk factors for adverse events and screening protocols to maximize patient safety. Personalized therapeutic plans developed through effective partnership between endocrinologists and ophthalmologists aim to enhance the safety and outcomes of TED treatments and improve care for this complex disease. CONCLUSION: TED management is shifting to an era of targeted therapy with multidisciplinary care. Teprotumumab has demonstrated superior efficacy to conventional treatments and has transformed our therapeutic and surgical algorithms. Clinical guidelines and additional studies are needed to further guide and refine therapy.

An Outperforming Artificial Intelligence Model to Identify Referable Blepharoptosis for General Practitioners.

The aim of this study is to develop an AI model that accurately identifies referable blepharoptosis automatically and to compare the AI model's performance to a group of non-ophthalmic physicians. In total, 1000 retrospective single-eye images from tertiary oculoplastic clinics were labeled by three oculoplastic surgeons as having either ptosis, including true and pseudoptosis, or a healthy eyelid. A convolutional neural network (CNN) was trained for binary classification. The same dataset was used in testing three non-ophthalmic physicians. The CNN model achieved a sensitivity of 92% and a specificity of 88%, compared with the non-ophthalmic physician group, which achieved a mean sensitivity of 72% and a mean specificity of 82.67%. The AI model showed better performance than the non-ophthalmic physician group in identifying referable blepharoptosis, including true and pseudoptosis, correctly. Therefore, artificial intelligence-aided tools have the potential to assist in the diagnosis and referral of blepharoptosis for general practitioners.

Corneal Neurotization via Dual Nerve Autografting.

Corneal neurotization is a fast-evolving surgical procedure for sensory reinnervation in neurotrophic keratopathy. After neurotization, prior reports document return of corneal sensation on average 8 months after surgery with 38 mm of sensation gain measured via cochet bonnet esthesiometer testing. Here, the authors describe a dual nerve grafting approach via simultaneous parallel sural nerve grafts from both the supratrochelar and supraorbital nerves to the affected contralateral cornea with return of sensation by postoperative week 11.

Microphthalmia and orbital cysts in DiGeorge syndrome.

We report the case of a 4-month-old boy diagnosed with DiGeorge syndrome with novel ocular features. The patient was diagnosed through genetic testing, with a noted 22q11.2 deletion, and had the additional clinical findings of cardiac anomalies, Hirschsprung's disease, and intracranial microhemorrhages. Eye findings included bilateral microphthalmia, persistent fetal vasculature, chorioretinal coloboma, and a unilateral orbital cyst. Given no known additional inciting exposures, a dysgenic mechanism resulting in failed closure of developmental fissures associated with the chromosomal deletion likely gave rise to these combined pathologies.

Thyroid Eye Disease: Navigating the New Treatment Landscape.

Thyroid eye disease (TED) is a complex inflammatory disease that can have a long clinical course with sight-threatening and debilitating ocular sequelae. Until recently, there were limited therapeutic options available. In the last decade we have gained a deeper understanding of the underlying pathophysiology, which has led to the development of novel effective targeted therapies. This article discusses the challenges encountered in the clinical evaluation and treatment of TED patients, with the goal to empower endocrinologists and ophthalmologists to work together to provide effective multidisciplinary care. We will review recommendations of past clinical guidelines around evaluation and management of TED patients, discuss the randomized controlled trials of new biologic therapies, and explore how to navigate the emerging therapeutic landscape.

A deep learning approach to identify blepharoptosis by convolutional neural networks.

PURPOSE: Blepharoptosis is a known cause of reversible vision loss. Accurate assessment can be difficult, especially amongst non-specialists. Existing automated techniques disrupt clinical workflow by requiring user input, or placement of reference markers. Neural networks are known to be effective in image classification tasks. We aim to develop an algorithm that can accurately identify blepharoptosis from a clinical photo. METHODS: A total of 500 clinical photographs from patients with and without blepharoptosis were sourced from a tertiary ophthalmic center in Taiwan. Images were labeled by two oculoplastic surgeons, with an independent third oculoplastic surgeon to adjudicate disagreements. These images were used to train a series of convolutional neural networks (CNNs) to ascertain the best CNN architecture for this particular task. RESULTS: Of the models that trained on the dataset, most were able to identify ptosis images with reasonable accuracy. We found the best performing model to use the DenseNet121 architecture without pre-training which achieved a sensitivity of 90.1 % with a specificity of 82.4 %, compared to the worst performing model which was used a Resnet34 architecture with pre-training, achieving a sensitivity of 74.1 %, and specificity of 63.6 %. Models with and without pre-training performed similarly (mean accuracy 82.6 % vs. 85.8 % respectively, p = 0.06), though models with pre-training took less time to train (1-minute vs. 16 min, p < 0.01). CONCLUSIONS: We report the use of AI to accurately diagnose blepharoptosis from a clinical photograph with no external reference markers or user input requirement. Most current-generation CNN architectures performed reasonably on this task, with the DenseNet121, and Resnet18 architectures without pre-training performing best in our dataset.

Neurostimulation for tear production.

PURPOSE OF REVIEW: Dry eye disease (DED) is a chronic multifactorial disease that affects millions of people worldwide. Despite ongoing research, treatment for DED remains a challenge. Neurostimulation for tear production is a rapidly evolving field that culminated in the development of the intranasal tear neurostimulator (ITN). In this article, we review the neuroanatomy and pathophysiology of tear production and the evolution of neurostimulation for the treatment of DED. RECENT FINDINGS: The ITN was approved for commercial use in April 2017. This innovation stemmed from the success of lacrimal nerve and anterior ethmoid nerve stimulation animal studies. Since then, numerous pilot studies and multicenter randomized controlled trials demonstrate increased aqueous tear production, improved DED-related symptoms, and device safety. Recent studies also report the positive effects of intranasal stimulation on mucin and lipid secretion. SUMMARY: Neurostimulation for enhanced tear production is a promising new treatment option for DED. Stimulation of the lacrimal nerve and anterior ethmoid nerve both effectively increase tear volume. The ITN is a noninvasive device that effectively increases aqueous tear volume and may improve tear composition, including mucin and lipid concentrations. Further studies are needed to determine proper patient selection and the long-term efficacy of neurostimulation for DED.