Association of Somatic TET2 Mutations With Giant Cell Arteritis.

OBJECTIVE: Giant cell arteritis (GCA) is an age-related vasculitis. Prior studies have identified an association between GCA and hematologic malignancies (HMs). How the presence of somatic mutations that drive the development of HMs, or clonal hematopoiesis (CH), may influence clinical outcomes in GCA is not well understood. METHODS: To examine an association between CH and GCA, we analyzed sequenced exomes of 470,960 UK Biobank (UKB) participants for the presence of CH and used multivariable Cox regression. To examine the clinical phenotype of GCA in patients with and without somatic mutations across the spectrum of CH to HM, we performed targeted sequencing of blood samples and electronic health record review on 114 patients with GCA seen at our institution. We then examined associations between specific clonal mutations and GCA disease manifestations. RESULTS: UKB participants with CH had a 1.48-fold increased risk of incident GCA compared to UKB participants without CH. GCA risk was highest among individuals with cytopenia (hazard ratio [HR] 2.98, P = 0.00178) and with TET2 mutation (HR 2.02, P = 0.00116). Mutations were detected in 27.2% of our institutional GCA cohort, three of whom had HM at GCA diagnosis. TET2 mutations were associated with vision loss in patients with GCA (odds ratio 4.33, P = 0.047). CONCLUSIONS: CH increases risk for development of GCA in a genotype-specific manner, with the greatest risk being conferred by the presence of mutations in TET2. Somatic TET2 mutations likewise increase the risk of GCA-associated vision loss. Integration of somatic genetic testing in GCA diagnostics may be warranted in the future.

Hyperglobus and Pseudoptosis in Type 1 Lipogenic Thyroid Eye Disease.

Purpose: We present a case of Type 1 (lipogenic) Thyroid Eye Disease (TED) and our aim is to describe an atypical presentation of a rare orbital process. Observations: A man in his 50s presented with left-sided eyelid drooping. His exam showed no evidence of active inflammation but did show left hyperglobus and ipsilateral upper eyelid pseudoptosis. He had no prior history or symptoms of Graves' Disease and imaging did not show evidence of extraocular muscle enlargement, bony asymmetries, or masses in the orbit. Subsequent lab work showed a low TSH (thyroid-stimulating hormone), elevated free T4 (thyroxine) and T3 (triiodothyronine), and elevated TSI (thyroid-stimulating immunoglobulin) index. Conclusions and importance: This is a unique and atypical presentation of a patient diagnosed with Type 1 (lipogenic) TED causing hyperglobus and pseudoptosis secondary to fat expansion in the absence of other classic TED findings such as contralateral eyelid retraction or extraocular muscle enlargement. Thyroid eye disease can have a heterogenous disease presentation, as evidenced by this case, and should always be considered in the differential diagnosis of pseudoptosis.

Reduction in Extraocular Muscle Cross-sectional Area and Correlation With Extraocular Motility and Diplopia Following Teprotumumab for Thyroid Eye Disease.

PURPOSE: To quantify changes in extraocular muscle (EOM) cross-sectional areas (CSA) on orbital imaging in patients with thyroid eye disease before and after teprotumumab treatment, and assess for correlation with clinical outcomes. METHODS: This retrospective study included thyroid eye disease patients treated with teprotumumab who had pre- and post-treatment CT imaging. Reformatted oblique coronal images were created for each orbit in a plane perpendicular to the optic nerve. EOM CSA measurements were performed by 2 radiographic reviewers and averaged. Primary outcomes included change in ratio of total EOM to orbit CSA, and of each individual muscle group to orbit CSA, before and after treatment. Secondary outcomes included subanalysis based on age (≥40, <40 years) and Clinical Activity Score (CAS) (≥4, <4), and comparison with clinical outcomes including CAS, Hertel exophthalmometry, Gorman diplopia score, and extraocular motility. RESULTS: Forty-eight orbits of 24 patients (16 female, mean age 57.9 years) were included. There was a significant reduction in the total EOM to orbit CSA ratio ( p < 0.01) and for each individual rectus muscle to orbit CSA ratio ( p < 0.01 for all groups). Total EOM to orbit CSA ratios were reduced for 21 patients (87.5%); this was statistically significant in 13 patients (54.2%). There was significant improvement in CAS, proptosis, diplopia, and EOM motility ( p < 0.01 for all categories). There was a significant correlation between reduction of EOM CSA, and reduction of diplopia ( p < 0.01) and EOM motility ( p < 0.01). CONCLUSIONS: EOM CSA is significantly reduced following treatment with teprotumumab, and correlates with clinical findings including improvement in extraocular motility and diplopia.

Smoking Is Associated With a Higher Risk of Surgical Intervention for Thyroid Eye Disease in the IRIS Registry.

PURPOSE: To describe the association of smoking status with surgical intervention for thyroid eye disease (TED) at the population-level. DESIGN: Retrospective cohort study. METHODS: This study included all adults (aged ≥18 years) with Graves disease in the Intelligent Research in Sight (IRIS) Registry (January 1, 2013, to December 31, 2020). The primary outcome was surgical intervention for TED, stratified into orbital decompression, strabismus surgery, and eyelid recession surgery. The Kaplan-Meier estimated 5-year cumulative probability for each surgical intervention was calculated. Multivariable Cox regression was used to evaluate the association between smoking status and each surgical intervention, adjusting for age, sex, race, ethnicity, and geographic region. RESULTS: This study included 87,774 patients. Median age was 59 years (IQR, 48-68 years); 81% were female patients. Current smokers had a greater 5-year cumulative probability of orbital decompression (3.7% vs 1.9%; P < .001), strabismus surgery (4.6% vs 2.2%; P < .001), and eyelid recession (4.1% vs 2.6%; P < .001) compared to never smokers. After adjusting for demographic factors, current smokers were at greater risk for orbital decompression (hazard ratio [HR], 2.1; 95% CI, 1.8-2.4; P < .001), strabismus surgery (HR, 2.0; 95% CI, 1.8-2.3; P < .001), and eyelid recession (HR, 1.7; 95% CI, 1.5-1.9; P < .001) than never smokers. Former smokers were at higher risk for each type of surgery for TED, albeit at lower levels than current smokers. CONCLUSIONS: Smoking was associated with increased risk of surgical intervention for TED in the IRIS Registry. Former smokers were at a lower risk than current smokers, supporting the role of smoking cessation on lowering the burden of surgical disease at the population-level.

Outcomes of Patients With Thyroid Eye Disease Partially Treated With Teprotumumab.

PURPOSE: In response to the coronavirus (COVID-19) pandemic, teprotumumab production was temporarily halted with resources diverted toward vaccine production. Many patients who initiated treatment with teprotumumab for thyroid eye disease were forced to deviate from the standard protocol. This study investigates the response of teprotumumab when patients receive fewer than the standard 8-dose regimen. METHODS: This observational cross-sectional cohort study included patients from 15 institutions with active or minimal to no clinical activity thyroid eye disease treated with the standard teprotumumab infusion protocol. Patients were included if they had completed at least 1 teprotumumab infusion and had not yet completed all 8 planned infusions. Data were collected before teprotumumab initiation, within 3 weeks of last dose before interruption, and at the visit before teprotumumab reinitiation. The primary outcome measure was reduction in proptosis more than 2 mm. Secondary outcome measures included change in clinical activity score (CAS), extraocular motility restriction, margin reflex distance-1 (MRD1), and reported adverse events. RESULTS: The study included 74 patients. Mean age was 57.8 years, and 77% were female. There were 62 active and 12 minimal to no clinical activity patients. Patients completed an average of 4.2 teprotumumab infusions before interruption. A significant mean reduction in proptosis (-2.9 mm in active and -2.8 mm in minimal to no clinical activity patients, P < 0.01) was noted and maintained during interruption. For active patients, a 3.4-point reduction in CAS ( P < 0.01) and reduction in ocular motility restriction ( P < 0.01) were maintained during interruption. CONCLUSIONS: Patients partially treated with teprotumumab achieve significant reduction in proptosis, CAS, and extraocular muscle restriction and maintain these improvements through the period of interruption.

Bilateral enlargement of all extraocular muscles: a presenting ophthalmic sign of hematologic malignancy.

Hematologic malignancies such as leukemia and lymphoma can frequently present in the orbit; however, involvement of the extraocular muscles is rare. The authors report two cases of systemic hematologic malignancy presenting with bilateral extraocular muscle enlargement and associated compressive optic neuropathy (CON). Both patients experienced clinical and radiographic improvement of ocular and systemic manifestations of disease with prompt initiation of targeted chemotherapy. These cases highlight the importance of including hematologic malignancy in the differential diagnosis of atypical bilateral extraocular muscle enlargement.

Wells Syndrome Presenting as Atypical Periorbital Cellulitis.

A 62-year-old man presented with diffuse, painless, left-sided preseptal edema, erythema, and woody induration extending to the left temple. The induration generated an orbital compartment syndrome with markedly elevated intraocular pressure necessitating lateral canthotomy and cantholysis. Although atypical for an infectious etiology, empiric broad-spectrum intravenous antibiotics were initiated with no improvement. A tissue biopsy demonstrated extensive perivascular and interstitial eosinophils with focal flame figures, and the patient was diagnosed with a severe hypersensitivity reaction or eosinophilic cellulitis (Wells syndrome). The disease process remitted rapidly upon initiation of oral prednisone. Wells syndrome is a rare inflammatory eosinophilic dermatosis, most often presenting in the limbs and trunk, with few reports of facial and periorbital involvement. This case highlights the importance of considering Wells syndrome in the differential diagnosis of atypical periorbital cellulitis that is nonresponsive to antibiotics and reviews the clinicopathologic nature of this disease.

Posterior Ischemic Optic Neuropathy in the Setting of Cocaine-Induced Orbital and Sinonasal Inflammation.

Intranasal cocaine abuse can lead to significant sinus and orbital complications, including optic neuropathy. A 46-year-old man with a history of recurrent cocaine-induced sino-orbital inflammation and infection with bony destruction presented with acute, painless, vision loss. Examination revealed no light perception vision. MRI of the orbits demonstrated new restricted diffusion of the right optic nerve on diffusion-weighted imaging and apparent diffusion coefficient sequences, consistent with posterior ischemic optic neuropathy. This is the first among cases of cocaine-induced optic neuropathy in the literature to illustrate ischemic changes on MRI in the optic nerve, highlighting the utility of diffusion-weighted imaging/apparent diffusion coefficient sequences when optic neuropathy is suspected and further suggesting an underlying ischemic etiology in similar cases.

Orbital Inflammation Following COVID-19 Vaccination.

Three patients presented with periorbital swelling, pain with extraocular movements, and binocular diplopia 1-4 days after receiving an mRNA Coronavirus Infectious Disease-19 (COVID-19) vaccine (BNT162b2, Pfizer/BioNTech; mRNA-1273, Moderna). All patients had a normal afferent function, unilateral limitation of extraocular motility, proptosis, and periorbital inflammation. Neuroimaging of the orbits with contrast revealed inflammation and enlargement of extraocular muscles in 2 cases and the lacrimal gland in 1 case. In all 3 cases, an extensive infectious and inflammatory laboratory work-up was unremarkable and signs and symptoms of orbital inflammation rapidly improved to complete resolution after treatment with high-dose oral prednisone. This is the first reported series of orbital inflammation occurring shortly after administration of the COVID-19 vaccine. Clinicians may consider an inflammatory postvaccine etiology as an alternative to presumed idiopathic diagnosis in such cases.

Shewanella algae Causing Pediatric Orbital Abscess With Leptomeningitis.

A 13-year-old boy presented with 3 days of left-sided periorbital pain, swelling, mucoid discharge, and fever to 103°F, with onset 1 day after swimming in the ocean. Within 12 hours, he experienced rapid clinical deterioration with formation of a superomedial subperiosteal abscess and an epidural abscess with leptomeningitis despite treatment with broad-spectrum intravenous antibiotics. The patient underwent urgent left orbitotomy with abscess drainage and functional endoscopic sinus surgery. Intraoperative cultures grew Shewanella algae and Escherichia coli . The patient showed marked clinical improvement following surgical intervention and tailored antibiotic therapy. This is the first reported case of orbital abscess with acute bacterial rhinosinusitis due to infection with Shewanella algae .

Lower eyelid malposition following repair of complex orbitofacial trauma.

PURPOSE: To compare the incidence of lower eyelid malposition following repair of isolated orbital floor fractures with that of complex orbitofacial fractures (defined as multi-wall fractures or prior orbital fracture repairs requiring revision) by oculofacial plastic surgeons via a transconjunctival or swinging eyelid approach. METHODS: Retrospective review of 175 patients who underwent surgical repair of orbital fractures at our institution. The primary outcomes were the occurrence of lower eyelid malposition (ectropion, entropion, and eyelid retraction) and the need for subsequent surgical correction. RESULTS: Of 95 patients with isolated orbital floor fractures, 4 developed eyelid malposition (4.2%), 1 of which required surgical repair (1.1%). Of 80 patients with complex orbitofacial fractures (48 multi-wall fractures, 32 secondary revisions), 10 had pre-operative eyelid malposition and were excluded from further analysis. Fourteen of the remaining 70 patients developed postoperative eyelid malposition (20%), 3 of which required surgical repair (4.3%). The difference in the occurrence of eyelid malposition between groups was statistically significant (p = .001), but the difference in rates of those requiring subsequent repair was not (p = .182). There was no statistically significant difference in the occurrence of eyelid malposition when considering other surgical factors including lateral canthotomy, conjunctival closure, implant material, or anterior rim screws. CONCLUSIONS: The incidence of lower eyelid malposition following orbital fracture repair via a fornix-based approach was significantly higher for the repair of complex orbitofacial fractures than for isolated floor fractures. However, very few patients in either group required surgical repair for eyelid malposition. Surgical factors including implant material did not affect outcomes.

Teprotumumab for the treatment of mild compressive optic neuropathy in thyroid eye disease: A report of two cases.

PURPOSE: To report two cases of thyroid eye disease (TED) associated compressive optic neuropathy (CON) that resolved after treatment with teprotumumab. OBSERVATION: Two patients presented with active TED resulting in mild CON with the typical corresponding visual field (VF) defects. Both patients were initiated on intravenous (IV) corticosteroid therapy but despite treatment had persistent VF defects. Both patients were then treated with teprotumumab and demonstrated marked clinical improvement and complete resolution of TED-CON VF defects early in their infusion course. CONCLUSIONS AND IMPORTANCE: These cases suggest that teprotumumab can be a rapid and effective treatment for TED-CON, and raises the question of whether it may be superior to IV corticosteroid therapy.

The Endoscopic Transnasal Approach to Orbital Tumors: A Review.

Historically, surgical access to orbital tumors has required a transcutaneous, transconjunctival or transcranial approach. Resection of orbital tumors is notoriously challenging due to the surrounding dense network of critical structures in a confined bony cavity. Advances in endoscopic endonasal surgery, initially used for sinonasal and skull base conditions, have allowed for expansion of its applications beyond the sinorbital interface. In the past decade, the evolution of techniques has enabled a purely endoscopic, minimally invasive approach to medially located orbital pathology with good outcomes. With experience and multidisciplinary collaboration between orbit and rhinologic surgeons, this has expanded to allow for a safe and effective transnasal approach to nearly all regions of the orbit with or without assistance from the orbital side. This review summarizes the relevant anatomy, variations of surgical approaches, and literature regarding outcomes of the endoscopic endonasal approach to orbital tumors.

Sclerosing Signet Ring Cell Carcinoma of the Lacrimal Gland: A Potentially New Primary Entity.

An 88-year-old man presented with diplopia, limitation of extraocular movements, and a firm palpable mass in the superolateral orbit. Biopsy revealed a sclerosing signet ring cell carcinoma with histopathologic features mimicking those of a primary signet ring cell (histiocytoid) carcinoma of the eyelid of eccrine or apocrine gland origin, a metastasis from an invasive lobular breast carcinoma or a metastatic diffuse-type gastric carcinoma. An extensive panel of immunohistochemical stains and molecular genetic analyses unequivocally failed to establish a precise diagnosis. Electron microscopy demonstrated features of a primary lacrimal gland lesion with intracytoplasmic lumens and zymogen granules typical of lacrimal secretory pyramidal cells. A thorough initial systemic work-up failed to reveal a primary visceral malignancy. Fifteen months of follow-up have failed to detect the emergence of another primary malignancy. To the best of our knowledge, a tumor with the morphology of the current lesion has not been previously described in the major or accessory lacrimal glands.

A conjunctival-sparing surgical technique for lower eyelid cicatricial entropion repair in ocular cicatricial pemphigoid.

Purpose: To present five cases of lower eyelid cicatricial entropion secondary to ocular cicatricial pemphigoid (OCP) successfully repaired with a conjunctival-sparing surgical technique.Methods: The records of one surgeon (SKF) were reviewed to identify patients with lower eyelid cicatricial entropion secondary to OCP who underwent repair with a conjunctival-sparing technique between September 1, 2016 and October 18, 2017. The medical records were reviewed and extracted data included: age, gender, past medical history, current medical and OCP status, clinical examination, details of entropion repair surgery, and outcome.Results: Five patients (three female, two male) were included with ages ranging from 44 to 93 years. All had biopsy proven OCP, which was in remission at the time of surgery, and all were currently receiving immunomodulatory medications. All patients were symptomatic from cicatricial entropion secondary to OCP and underwent successful lower eyelid entropion repair with a conjunctival-sparing technique described herein, involving infraciliary rotation with suture fixation of the orbicularis muscle to the tarsus. Other contributing mechanisms of eyelid malposition including horizontal eyelid laxity and orbicularis oculi override were addressed simultaneously with lateral tarsal plication or orbicularis muscle debulking, resulting in 100% anatomic success and relief of symptoms with no cases of OCP reactivation, and with good durability with an average 13.9 months follow up (range 6.5-22 months).Conclusions: Successful repair of lower eyelid cicatricial entropion in immunomodulated patients with OCP can be achieved without disease reactivation using a surgical technique that spares the conjunctiva and lower eyelid retractors.