The Role of Insulin-like Growth Factor-1 and Its Receptor in the Eye: A Review and Implications for IGF-1R Inhibition.

PURPOSE: FDA approval of teprotumumab for thyroid eye disease in January 2020 reinforced interest in the pharmacologic potential of insulin-like growth factor-1 (IGF-1) and its receptor, IGF-1R. Despite recent approval and adaptation for ophthalmic use, IGF-1R inhibitors are not a new therapeutic class. In 1986, Yamashita described aIR3, a monoclonal antibody to IGF-1R (anti-IGF-1R), that inhibited the effect of IGF-1 on growth hormone release. Given the widespread presence of IGF-1R, interrupting this receptor can lead to systemic physiologic effects, some adverse. We aim to review what is known about IGF-1/IGF-1R in the eye and consider the possible local side effects, unintended consequences, and potential uses of this medication class. METHODS: A PubMed database search utilizing the keywords "insulin-like growth factor-1, eye, inhibitor, antibody, side effect" was performed to identify publications discussing IGF-1 in the human eye from January 2011 to August 2021. Criteria for acceptance included studies discussing human subjects or human tissue specifically related to the eye. RESULTS: Out of a total of 230 articles, 47 were organized in 3 subject groups for discussion: thyroid-associated orbitopathy, cornea and the ocular surface, and the retina and neovascularization. Review of the literature demonstrated that IGF-1 affects growth and development of the eye, epithelial proliferation, retinal angiogenesis, inflammation, and is associated with thyroid-associated orbitopathy. CONCLUSIONS: IGF-1R exists throughout in the human body, including the cornea, retina, and orbit. Research regarding ocular effects of IGF-1/IGF-1R outside thyroid eye disease is limited. Carefully designed studies and clinical assessments of patients undergoing treatment with anti-IGF-1R may identify ocular side effects and foster consideration of the role of anti-IGF-1R in ocular therapeutics. Given the increasing use of anti-IGF-1R antibodies, understanding their ocular effects, side effects, and potential systemic implications for use in disease is critical.

Optical Device to Improve Eyelid Surgery.

Background. Obtaining symmetry is one of the most critical challenges of bilateral blepharoplasty surgery. Current techniques rely on caliper measurements and the "eye" of the surgeon. This is time-consuming and prone to error. There is a need for a precise and cost-effective surgical guide. Objective. The purpose of this experimental study was to design a device to improve the accuracy of markings in blepharoplasty. Methods. The device, a combination of a camera and pico-projector, creates a mirror image of the marked eye that is projected onto the second eye with a light beam. This allows the reference features in the captured image to be overlaid precisely on the respective features in the second eye. The device concept was tested initially on a mannequin and then on eleven human volunteer subjects. No actual surgeries were performed. The accuracy of the markings was assessed by comparing optical images of one eye to another via a specifically designed computer analysis. Results. The results of this study revealed that the accuracy of guided blepharoplasty markings was superior to that of unguided markings. Conclusion. The proposed device has a potential to improve precision of symmetrical surgical marking in blepharoplasty surgery, greatly reduce surgeon's time and effort, and ultimately contribute to successful patient outcomes and satisfaction. Additional modifications are forthcoming to prepare the device for clinical use.

Examining the Role of Retrobulbar Hyaluronidase in Reversing Filler-Induced Blindness: A Systematic Review.

PURPOSE: To provide a systematic review of the literature concerning retrobulbar hyaluronidase injections as a treatment for hyaluronic acid gel filler-induced blindness and evaluate the level of evidence for this proposed therapy. METHODS: The authors performed a search of English language articles published on the use of retrobulbar hyaluronidase to reverse vision loss precipitated by hyaluronic acid gel fillers. Articles reviewed included case reports/series, experimental investigations, expert opinion commentaries, and major reviews. To date, there have been no case-control, cohort, or randomized control studies to evaluate this treatment. Five anecdotal descriptions of hyaluronic acid gel filler blindness treated specifically with retrobulbar hyaluronidase were identified, for a total of 9 patients. One hundred twelve articles in total on this treatment and related topics, including filler-induced blindness and alternative treatments, were identified and reviewed. RESULTS: Of the 9 documented cases of patients treated with retrobulbar hyaluronidase for hyaluronic acid-induced blindness, visual improvement was demonstrated in 2 cases. The successes, however, are undermined by inconsistent pretreatment ophthalmic assessment and documentation. Animal studies demonstrate mixed results. Laboratory studies document the inability of hyaluronidase to cross the optic nerve sheath. CONCLUSIONS: There is not currently enough evidence to support retrobulbar hyaluronidase as a treatment for filler-induced blindness. Additional studies are needed to further evaluate its efficacy and explore alternative treatments.

Lenalidomide-Associated Thyroid-Related Eyelid Retraction.

Several antineoplastic treatments have been responsible for thyroid dysfunction and thyroid eye disease. Min, Vaidya, and Becker (2011) reported a case of euthyroid Graves orbitopathy after treatment with ipilimumab with the patient displaying proptosis and myositis in the setting of normal thyroid function tests and elevated thyroid antibodies. The authors report a case of a 76-year-old woman who developed right upper lid retraction and proptosis after 2.5 years of treatment with lenalidomide for multiple myeloma. Thyroid function tests were normal: thyroid-stimulating hormone 0.808 mIU/mL, total T3 102 ng/dL, free T4 1.48 ng/dL. Thyroid antibodies were elevated: thyrotropin receptor antibody 2.26 IU/L, thyroglobulin antibody 1043.1 IU/mL, and thyroid peroxidase antibody 38 IU/mL. A nuclear medicine thyroid scan was normal. Given the possible thyroid effects from lenalidomide, patients who receive this medication should be periodically evaluated for thyroid dysfunction and thyroid eye disease.

Inflammatory Mediators in Xanthelasma Palpebrarum: Histopathologic and Immunohistochemical Study.

PURPOSE: To evaluate the expression of inflammatory mediators in xanthelasma palpebrarum. METHODS: In this retrospective histopathologic case-control study, xanthelasma specimens obtained from the private practice and pathology archives of 1 author (R.Z.S.) were analyzed and compared with the blepharoplasty tissues from age- and sex-matched controls. Paraffin-embedded tissue sections were stained with hematoxylin-eosin and CD3, CD20, CD163, cyclooxygenase-1, inducible nitric oxide synthase, matrix metallopeptidase-9, and myeloperoxidase antibodies. Immunostaining was quantified by light microscopy and with a computerized image analysis system of scanned images. RESULTS: Hematoxylin-eosin-stained preparations of xanthelasma specimens demonstrated significantly more intense chronic lymphocytic infiltrate when compared with the control blepharoplasty tissues (p < 0.001). Immunohistochemical studies revealed more intense CD3+ T cell and CD163+ histiocytic infiltrate (11% vs. 5%; p = 0.02 and 28% vs. 5%; p = 0.003, respectively) and increased expression of cyclooxygenase-1 (44% vs. 20% expressing cells; p < 0.001 and 21% vs. 9% strongly expressing cells; p = 0.008) and inducible nitric oxide synthase (43% vs. 26% expressing cells; p = 0.03 and 42% vs. 25% strongly expressing cells; p = 0.02) in xanthelasma specimens compared with control tissues. CONCLUSIONS: The inflammatory milieu in xanthelasma appears to be analogous to descriptions of the early stages of cardiac atherosclerotic plaque formation. These findings may contribute to the understanding of xanthelasma pathogenesis and to the development of potential targeted therapies.

Clinical Response to Tocilizumab in Severe Thyroid Eye Disease.

Tocilizumab, in a preliminary study, was reported to be an effective therapy for moderate to severe thyroid eye disease. The authors describe the clinical response of 2 severe thyroid eye disease cases refractory to intravenous steroids and orbital decompression. Both patients demonstrated improved clinical activity scores with minimal side effects after tocilizumab therapy. In addition, post tocilizumab orbital fat biopsies demonstrated benign adipose tissue without evidence of inflammatory cells.

Predicting the Development of Orbitopathy in Graves Thyroidopathy Patients: The Potential Role of TSI Testing.

OBJECTIVE: To determine whether thyroid-stimulating immunoglobulin (TSI) testing can predict the risk of development of Graves orbitopathy in newly diagnosed Graves thyroidopathy patients. DESIGN: Retrospective cohort, from 2008 to 2013. SETTING: The Thyroid Referral Center at California Pacific Medical Center. PARTICIPANTS: A retrospective cohort of newly diagnosed Graves thyroidopathy patients from the California Pacific Medical Center Thyroid Referral Center. Patients were included if they had TSIs drawn at or near the time of diagnosis of Graves thyroidopathy. Patients were excluded from the study if they had a long-standing diagnosis of Graves thyroidopathy, orbitopathy at time of diagnosis, no TSIs drawn, or follow up of less than 6 months. MAIN OUTCOME MEASURES: Patients were followed for the development of orbitopathy as determined by their endocrinologists. Results were adjusted for family history, smoking status, age, radioiodine ablation treatment, and race. RESULTS: Thirty-three patients met inclusion criteria out of a screened population of 506 patients. Eight out of 33 patients (24%) developed orbitopathy. The mean time from diagnosis of Graves' thyroidopathy to development of orbitopathy was 11.6 months (median: 7.5 months, range: 1 to 20 months). The mean initial TSI value was 421.3 in those that developed orbitopathy compared to 245.9 in those who had at least 6 months of documented follow-up and did not develop orbitopathy (p = 0.04). Those in the top tercile of initial TSI values were 14 times as likely to develop orbitopathy (relative risk (RR) = 14.0, p = 0.02; multivariate adjusted RR = 13.08, p = 0.03). Family history, smoking status, age, radioiodine ablation, thyroid-stimulating hormone, and race were not statistically significant predictors. CONCLUSIONS: TSI level greater than 400 at time of presentation of Graves thyroidopathy may be a useful predictor of risk for development of orbitopathy. This information will help to identify patients likely to benefit from early referral to an ophthalmologist for possible preemptive therapy to prevent the development of orbitopathy. Prospective cohort studies are needed to definitively establish the metrics for TSI as a predictor of orbitopathy.

Orbital B-lymphocyte depletion in a treatment failure of rituximab for thyroid eye disease.

Rituximab is an emerging treatment for thyroid eye disease. Rituximab effectively depletes circulating CD20+ B-lymphocytes; however, its effect on target tissues has not been well-studied. Failures of rituximab have been infrequently reported. The authors describe a patient treated with rituximab for thyroid eye disease who failed to respond to treatment, and underwent orbital decompression. Orbital fat samples and peripheral blood samples were evaluated for the presence of CD20+ B-lymphocytes. Complete depletion of CD20+ B-lymphocytes was demonstrated in both the orbit and the blood. This case demonstrates that rituximab effectively depletes orbital CD20+ B-lymphocytes, and this depletion was maintained for 2 months despite a clinical deterioration.

IgG4-related disease presenting with profound bilateral orbital and adnexal inflammation.

Purpose: IgG4-related disease is an immune-mediated fibroinflammatory condition that can affect almost every major organ system. Orbital and adnexal involvement in IgG4-related disease though not uncommon can be varied depending on the site of the lymphoplasmacytic infiltration. This case of profound bilateral orbital inflammation is presented to demonstrate the significant clinical manifestations of IgG4-related ophthalmic disease. Observations: A 52-year-old man with a remote and seemingly unrelated history of lymphadenopathy presented to the Oculoplastics clinic with massive bilateral upper and lower lid swelling and induration. Hematologic testing demonstrated an elevation in serum IgG4 - a non-specific finding seen in various infectious, inflammatory, and malignant processes. Imaging demonstrated diffuse enlargement of orbital structures, including the lacrimal glands and extraocular muscles, as well as inflammatory changes of the adnexal and retrobulbar soft tissue. Orbital biopsy was required to confirm the diagnosis of IgG4-related ophthalmic disease. Conclusions and Importance: IgG4-related ophthalmic disease presents with various non-specific clinical signs and symptoms. The most common presentations include dacryoadenitis, enlarged orbital nerves, and orbital fat involvement; however, the extent of involvement both locally and systemically varies greatly. Clinical findings and imaging are helpful in narrowing the differential diagnosis; however, biopsy for histopathologic examination is essential to confirm IgG4-related disease. Physicians must maintain a high level of suspicion for the disease for proper management.

Bilateral primary orbital xanthogranulomas: A case report and comparison of xanthomatous conditions.

This report describes an unusual and diagnostically challenging case of subcutaneous soft tissue xanthogranulomas of bilateral orbits of a 58-year-old female patient seen in a private oculoplastics practice. Accurate and timely diagnosis is crucial in xanthogranulomatous diseases so that any systemic manifestations can be identified and addressed in a multidisciplinary fashion. Periorbital xanthogranuloma is a frequent early manifestation of adult xanthogranulomatous disease, and its association with life-threatening systemic disease requires accurate diagnosis and prompt work-up. This case describes an otherwise asymptomatic patient who presented with bilateral orbital masses causing visually significant ptosis, initially diagnosed as soft tissue xanthomas, and later identified as xanthogranulomas. It is important for physicians of all fields, from primary care to surgical subspecialty, to be aware that xanthogranulomatous disease may first present as periorbital lesions and/or orbital masses, and that further work-up for vision and life-threatening systemic disease is warranted.

Orbital lymphocyte populations in three states of thyroid eye disease.

Purpose: We report histopathologic orbital tissue analysis from three patients with thyroid eye disease (TED) - active, chronic, and post-teprotumumab to better characterize orbital cellular populations in these varying states of TED. Observations: Orbital tissues in TED demonstrate minimal lymphocytic infiltration in fat and Mueller's muscle. Following teprotumumab treatment, the tissues were devoid of lymphocytes with only perivascular cuffs of T-lymphocytes remaining in orbital fat. Conclusions and importance: In active TED, post-teprotumumab treatment, and in quiescent TED, orbital fat may not show significant inflammatory infiltration. More work is warranted to characterize specific cellular effects of teprotumumab and other biologics.

Idiopathic sclerosing dacryoadenitis.

Dacryoadenitis is an inflammation of the lacrimal gland. This condition has an extensive differential diagnosis, requiring a thorough workup to identify the underlying etiology. If no etiology is identified, the condition is termed idiopathic dacryoadenitis. The purpose of this report is to present a case of idiopathic sclerosing dacryoadenitis and review the diagnostic process.We present a case of sclerosing dacryoadenitis non responsive to systemic antibiotics and steroids, improving after surgical debulking/biopsy. Systemic inflammatory and infectious labs were negative. Tissue was negative for SARS-CoV-2 antigen. Histopathologic review of the surgical specimen revealed nonspecific, sclerosing dacryoadenitis, ultimately supporting the diagnosis of idiopathic nonspecific fibrosing dacryoadenitis.This case reviews the presentation, evaluation, and management of a common orbital pathologic condition, with updated recommendations based on the most current literature.