Bilateral Dilated Superior Ophthalmic Veins in a Patient With an Arteriovenous Dialysis Fistula.

A 64-year-old man presented with 4 months of diplopia. He had end-stage renal disease requiring a cephalic transposition brachiocephalic fistula that was no longer in use following successful renal transplantation. On presentation, he had bilateral proptosis, extraocular movement restriction, chemosis, tortuous episcleral vessels, and caruncular injection. Non-contrast CT of the orbits demonstrated dilation of both superior ophthalmic veins, and CT angiography showed asymmetric enlargement of both cavernous sinuses and superior ophthalmic veins. A carotid-cavernous fistula was suspected, but cerebral angiography revealed shunting from the old fistula with intracranial drainage and cerebral venous hypertension. Aberrant retrograde drainage resulted from anatomical compression of the left brachiocephalic vein. The fistula was ligated, and at 1-week follow-up, the patient had marked improvement in extraocular movements and orbital congestion with near complete resolution of diplopia. Postoperative CT angiography obtained 2 months later demonstrated decreased size of both superior ophthalmic veins, consistent with improvement of venous hypertension.

Establishment and Characterization of Three Human Ocular Adnexal Sebaceous Carcinoma Cell Lines.

Ocular adnexal sebaceous carcinoma (SebCA) represents one of the most clinically problematic periocular tumors, often requiring aggressive surgical resection. The pathobiology of this tumor remains poorly understood, and few models exist that are suitable for preclinical testing. The aim of this study was to establish new cell lines to serve as models for pathobiological and drug testing. With patient consent, freshly resected tumor tissue was cultured using conditional reprogramming cell conditions. Standard techniques were used to characterize the cell lines in terms of overall growth, clonogenicity, apoptosis, and differentiation in vitro. Additional analyses including Western blotting, short tandem repeat (STR) profiling, and next-generation sequencing (NGS) were performed. Drug screening using mitomycin-C (MMC), 5-fluorouricil (5-FU), and 6-Diazo-5-oxo-L-norleucine (DON) were performed. JHH-SebCA01, JHH-SebCA02, and JHH-SebCA03 cell lines were established from two women and one man undergoing surgical resection of eyelid tumors. At passage 15, they each showed a doubling time of two to three days, and all could form colonies in anchorage-dependent conditions, but not in soft agar. The cells contained cytoplasmic vacuoles consistent with sebaceous differentiation, and adipophilin protein was present in all three lines. STR profiling confirmed that all lines were derived from their respective patients. NGS of the primary tumors and their matched cell lines identified numerous shared mutations, including alterations similar to those previously described in SebCA. Treatment with MMC or 5-FU resulted in dose-dependent growth inhibition and the induction of both apoptosis and differentiation. MYC protein was abundant in all three lines, and the glutamine metabolism inhibitor DON, previously shown to target high MYC tumors, slowed the growth of all our SebCA models. Ocular adnexal SebCA cell lines can be established using conditional reprogramming cell conditions, and our three new models are useful for testing therapies and interrogating the functional role of MYC and other possible molecular drivers. Current topical chemotherapies promote both apoptosis and differentiation in SebCA cells, and these tumors appear sensitive to inhibition or MYC-associated metabolic changes.

Ocular adnexal sebaceous carcinoma in a patient with Li-Fraumeni syndrome.

Li-Fraumeni syndrome (LFS) is caused by a pathogenic germline variant at the TP53 locus and is associated with an increased predisposition to a variety of cancers. The neoplasms most frequently associated with LFS are sarcomas, breast cancer, brain tumors, and adrenocortical carcinomas. In this case report, we present a 43-year-old male diagnosed with an ocular adnexal sebaceous carcinoma of the right upper eyelid who was confirmed to have LFS with subsequent genetic testing. The mutational profile of both the patient's genetic screen and tumor sequencing were congruent, demonstrating the same pathogenic loss-of-function TP53 variant. This case report highlights the importance of pursuing genetic testing in patients with a history of multiple tumor types, particularly those with uncommon diagnoses. In this case, confirmation of LFS had important implications for personalized patient care, including identification of contraindicated treatment interventions and the imaging modalities necessary for vigilant follow-up screening.

Teprotumumab and Hearing Loss: Case Series and Proposal for Audiologic Monitoring.

PURPOSE: To present a protocol for audiologic monitoring in the setting of teprotumumab treatment of thyroid eye disease, motivated by 4 cases of significant hearing loss, and review the relevant literature. METHODS: Cases of hearing loss in the setting of teprotumumab were retrospectively elicited as part of a multi-institutional focus group, including oculoplastic surgeons, a neurotologist and an endocrinologist. A literature review was performed. RESULTS: An aggregate of 4 cases of teprotumumab-associated hearing loss documented by formal audiologic testing were identified among 3 clinicians who had treated 28 patients. CONCLUSIONS: Teprotumumab may cause a spectrum of potentially irreversible hearing loss ranging from mild to severe, likely resulting from the inhibition of the insulin-like growth factor-1 and the insulin-like growth factor-1 receptor pathway. Due to the novelty of teprotumumab and the lack of a comprehensive understanding of its effect on hearing, the authors endorse prospective investigations of hearing loss in the setting of teprotumumab treatment. Until the results of such studies are available, the authors think it prudent to adopt a surveillance protocol to include an audiogram and tympanometry before, during and after infusion, and when prompted by new symptoms of hearing dysfunction.

Detection of Human Papillomavirus in Squamous Lesions of the Conjunctiva Using RNA and DNA In-Situ Hybridization.

In-situ hybridization provides a convenient and reliable method to detect human papillomavirus (HPV) infection in formalin-fixed paraffin-embedded tissue. Cases of conjunctival papillomas, conjunctival intraepithelial neoplasia (CIN), conjunctival carcinoma in situ (cCIS), and invasive squamous cell carcinoma (SCC), in which low-risk (LR) and/or high-risk (HR) HPV types were evaluated by RNA or DNA in-situ hybridization, were retrospectively identified. LR HPV types were frequently detected in conjunctival papillomas (25/30, 83%), including 17/18 (94%) with RNA probes, compared to 8/12 (75%) with DNA probes. None of the CIN/cCIS or SCC cases were positive for LR HPV by either method. HR HPV was detected by RNA in-situ hybridization in 1/16 (6%) of CIN/cCIS cases and 2/4 (50%) of SCC cases, while DNA in-situ hybridization failed to detect HPV infection in any of the CIN/cCIS lesions. Reactive atypia and dysplasia observed in papillomas was generally associated with the detection of LR HPV types. Collectively, our findings indicate RNA in-situ hybridization may provide a high-sensitivity approach for identifying HPV infection in squamous lesions of the conjunctiva and facilitate the distinction between reactive atypia and true dysplasia. There was no clear association between HPV infection and atopy in papillomas or dysplastic lesions.

Use of computer-assisted surgery in the orbit.

PURPOSE: To present the application of computer-assisted surgery (CAS) in pre-operative planning, intra-operative navigation, and post-operative assessment as an adjunct tool in orbital surgery. METHODS: An IRB-approved, retrospective review was performed to identify patients who had undergone orbital surgery by a single surgeon from July 2013 to December 2019 with attention to pre-operative virtual surgical planning, intra-operative navigation, and post-operative assessment. The reasons and methods of CAS use were classified. RESULTS: The use of computer-assisted technologies was identified in 91 cases out of 464 orbital surgeries (19.6%). This included 23 (25.3%) orbital decompression surgeries, 39 (42.9%) fracture repairs, and 25 (27.5%) orbital tumors. In all cases, pre-, intra-, and post-operative CAS allowed for increased operative efficiency and safety with good outcomes. CONCLUSIONS: Use of CAS in orbital surgery can allow for complex radiographic analysis and in select cases is a great tool to add to the orbital surgeon's armamentarium.

High-risk human papillomavirus and ZEB1 in ocular adnexal sebaceous carcinoma.

BACKGROUND: Ocular adnexal (OA) sebaceous carcinoma is an aggressive malignancy. Oncologic drivers of ocular sebaceous carcinoma are incompletely understood. METHODS: A retrospective search of our pathology archives for OA sebaceous carcinoma identified 18 primary resection specimens. Immunohistochemistry for p16 and ZEB1 and RNA in situ hybridization for high-risk human papillomavirus (HPV) subtypes were performed. RESULTS: High-risk HPV was demonstrated in 2/11 (18%) cases. p16 overexpression was observed in 10/11 (91%). No association between gender, age at presentation, tumor location, intraepithelial spread, tumor size, and T stage was observed between HPV-driven and nonviral cases. High expression of ZEB1 was observed in the intraepithelial component of 4/14 (28%) cases and in the subepithelial component of 1/13 (7%) cases. ZEB1 overexpression was not associated with HPV status, T stage, or tumor size. CONCLUSION: As previously described by others, our findings suggest that a subset of OA sebaceous carcinomas may arise via an HPV-dependent pathway. However, unlike high-risk HPV-driven carcinomas of the oropharynx, we did not identify an association between HPV-status and prognostic features. Furthermore, p16 expression was not a useful surrogate marker for HPV-driven disease. ZEB1 overexpression is not associated with HPV in our cohort of ocular sebaceous carcinoma.

Compound Coherent Plane-Wave Ultrasound Imaging of Vascular Malformations of the Orbit.

PURPOSE: Prior color-flow Doppler ultrasound studies of the eye have been performed with systems that exceed US Food and Drug Administration permissible ophthalmic ultrasonic energy limits. The authors report a study of orbital vascular malformations using a novel, Food and Drug Administration compliant, ultrafast compound coherent plane-wave ultrasound device to produce power Doppler images. METHODS: Using a Verasonics Vantage 128 ultrasound engine and a user-developed MATLAB program with a 5-MHz linear-array probe, compound coherent plane-wave ultrasound data were collected on patients with orbital vascular malformations. Real-time color-flow Doppler visualized orbital blood flow. Power Doppler images were produced by post-processing compound coherent plane-wave ultrasound data acquired continuously for 2 seconds. RESULTS: Compound coherent plane-wave ultrasound was performed on 3 orbital vascular malformations (1 venolymphatic malformation, 1 infantile hemangioma, and 1 arteriovenous malformation). Compound coherent plane-wave ultrasound produced a high-resolution depiction of orbital blood flow for orbital vascular malformations with high sensitivity to slow flow. CONCLUSIONS: Analysis of blood flow within orbital lesions informs treatment planning. Compound coherent plane-wave ultrasound is an emerging ultrasound modality that falls within the Food and Drug Administration guidelines for use in the orbit and provides information to characterize orbital vascular malformations.

Chocolate Cysts Associated With Porous Polyethylene Orbital Implants.

Late-onset orbital hemorrhage is a rare complication of alloplastic implant use in orbital wall reconstruction following trauma. The authors report 3 patients with chocolate cysts presenting 3 to 9 years after orbital fracture repair with porous polyethylene implants. All patients were managed by implant removal and evacuation of cyst contents. Complete excision of the cyst was performed in 1 patient, while partial excision of the capsule was performed in 2 patients. Improvement of symptoms associated with the mass effects of the cyst was noted after surgical intervention. The authors also report the first case of orbital volume expansion from a chocolate cyst associated with a nonbarriered porous polyethylene implant. Delayed hemorrhage with capsule formation, although extremely rare, is a possible complication following orbital fracture repair with porous polyethylene implants.

NGS Analysis Confirms Common TP53 and RB1 Mutations, and Suggests MYC Amplification in Ocular Adnexal Sebaceous Carcinomas.

Ocular adnexal (OA) sebaceous carcinomas generally demonstrate more aggressive clinical and histopathological phenotypes than extraocular cases, but the molecular drivers implicated in their oncogenesis remain poorly defined. A retrospective review of surgical and ocular pathology archives identified eleven primary resection specimens of OA sebaceous carcinomas with adequate tissue for molecular analysis; two extraocular cases were also examined. Next-generation sequencing was used to evaluate mutations and copy number changes in a large panel of cancer-associated genes. Fluorescence in situ hybridization (FISH) confirmed MYC copy number gain in select cases, and immunohistochemistry to evaluate MYC protein expression. The commonest mutations occurred in TP53 (10/13) and RB1 (7/13). Additional mutations in clinically actionable genes, or mutations with a frequency of at least 25%, included the NF1 (3/12), PMS2 (4/12), ROS1 (3/12), KMT2C (4/12), MNX1 (6/12), NOTCH1 (4/12), PCLO (3/12), and PTPRT (3/12) loci. Low level copy number gain suggestive of amplification of the MYC locus was seen in two cases, and confirmed using FISH. MYC protein expression, as assessed by immunohistochemistry, was present in almost all sebaceous carcinoma cases. Our findings support the concept that alterations in TP53 and RB1 are the commonest alterations in sebaceous carcinoma, and suggest that MYC may contribute to the oncogenesis of these tumors.

High-risk human papillomavirus positive primary squamous cell carcinoma of the lacrimal gland: a case report.

A 78-year-old Caucasian female presented with a painless mass in the right orbit that had progressively enlarged over several months. Computed tomography scan of the orbits showed a right lacrimal gland mass with no bony erosion. Histopathologic analysis of the biopsy specimen revealed invasive squamous cell carcinoma positive via in-situ hybridization for high-risk human papillomavirus. The patient underwent successful removal of the right lacrimal gland tumor en bloc, followed by adjuvant radiotherapy. This is an extremely rare case of primary squamous cell carcinoma of the lacrimal gland and the first report describing human papillomavirus positivity in this tumor location.

Age-Related Changes in the Clinical Phenotype of Compressive Optic Neuropathy in Thyroid Eye Disease.

PURPOSE: This study compares the age-related clinical features of thyroid eye disease-compressive optic neuropathy (TED-CON) to those with noncompressive disease (TED-NC). METHODS: A retrospective case series review of 165 orbits from 121 patients with TED-CON were compared with an age- and gender-matched cohort of 88 orbits from 44 patients with TED-NC with institutional review board approval. Clinical features including exophthalmos, dyschromatopsia, restricted ocular motility, visual acuity, and mean deviation on 24-2 Humphrey Visual Field were compared in 5 age groups. A previously validated formula, the Columbia TED-CON Diagnostic formula, used to mathematically predict the presence or absence of compressive optic neuropathy was applied, and the sensitivity and specificity of the formula was measured in each age group. RESULTS: Exophthalmos, dyschromatopsia, restricted ocular motility, and mean deviation on 24-2 Humphrey Visual Field vary significantly across age groups in patients with TED-CON. Conversely, only visual acuity and dyschromatopsia vary significantly across age groups in patients with TED-NC. There was a significant difference between the TED-CON and the TED-NC groups when comparing the 2 groups by decade. The Columbia TED-CON Diagnostic formula had high sensitivity and specificity (74-90%) in all age groups. CONCLUSIONS: This is the first study to date demonstrating the age-related variability of clinical characteristics in a large series of patients with either TED-CON or TED-NC. The clinical phenotype of TED-CON varies significantly by decade when examining exophthalmos, dyschromatopsia, ocular motility restriction, and mean deviation on 24-2 Humphrey Visual Field. These clinical characteristics are also significantly different when compared with a population of patients with TED-NC.

Predominant Contribution of Superior Rectus-Levator Complex Enlargement to Optic Neuropathy and Inferior Visual Field Defects in Thyroid Eye Disease.

PURPOSE: To compare extraocular muscle volumes in thyroid eye disease patients with and without compressive optic neuropathy. METHODS: A retrospective review of 44 orbital CT scans (28 orbits without compressive disease and 16 orbits with compressive optic neuropathy) was conducted. The extraocular muscle volumes, summated soft tissue volumes, and optic nerve volumes were calculated at a section in the posterior 1/3 of the orbit. The visual fields of the orbits with compressive optic neuropathy were analyzed. RESULTS: The mean combined extraocular muscle/summated soft tissue volume ratio and the mean superior rectus-levator complex/summated soft tissue volume ratio were greater in those with compressive optic neuropathy than in those without compressive optic neuropathy (p = 0.02, 0.008, respectively). The ratio of the mean inferior, medial, or lateral rectus/summated soft tissue volume did not differ significantly between patients with or without compressive optic neuropathy (p values of 0.315, 0.615, and 0.254, respectively). Visual field analysis of the compressive optic neuropathy group demonstrated that 58% of the orbits with visual field defects had inferior field defects. CONCLUSIONS: When measured at a section near the orbital apex, the mean combined muscle/summated soft tissue volume ratio and the mean superior rectus-levator complex/summated soft tissue volume ratio are greater in those with compressive disease than those without. This suggests that the specific enlargement of the superior rectus-levator complex makes a significant contribution to thyroid eye disease-compressive optic neuropathy and may explain the inferior visual field deficits classically found in this group of patients.

Doxycycline Injection for Sclerotherapy of Lower Eyelid Festoons and Malar Edema: Preliminary Results.

PURPOSE: To investigate the safety and efficacy of direct, intralesional doxycycline hyclate injection for improving the appearance of cosmetically significant lower eyelid festoons and malar edema. METHODS: An Institutional Review Board approved, retrospective review was performed of 15 consecutive patients with malar edema and/or festoons injected with doxycycline hyclate at a concentration of 10 mg/ml. Pre- and postinjection photographs were reviewed and graded on a scale of 0 to 3 (0: no festoon; 1: small festoon; 2: medium festoon; 3: large festoon) by 2 masked physician observers. Patients were excluded from the final analysis if they received an alternate dose concentration, had incomplete photographic records, or did not follow up. Student t test was used for statistical analysis. RESULTS: Twenty consecutive treatment areas of 11 patients were included in the analysis. Final follow up ranged from 3 to 104 weeks, with a mean follow up of 22.5 weeks. The average (standard deviation) initial festoon grade of 2.5 (0.58) decreased to 0.9 (0.82) with a p value of <0.001. The average number of injections performed per side was 1.4 (range: 1-2). The mean volume per injection was 0.72 ml (range: 0.15-2.0 ml). Commonly documented subjective complaints were burning sensation with injection, pain, bruising, and erythema. There were no other dermatologic or visual complications following treatment. CONCLUSIONS: These preliminary results suggest that intralesional injections of doxycycline hyclate at a concentration of 10 mg/ml may be an effective treatment option for cosmetically significant lower eyelid festoons and malar edema. Future prospective studies with increased patient numbers, increasing concentrations, combination therapies with local anesthetic or regional nerve blocks, and longer follow up are needed to validate these results and determine optimal injection technique.

The Columbia Thyroid Eye Disease-Compressive Optic Neuropathy Diagnostic Formula.

PURPOSE: Diagnosing thyroid eye disease-compressive optic neuropathy (TED-CON) is challenging, particularly in cases lacking a relative afferent pupillary defect. Large case series of TED-CON patients and accessible diagnostic tools are lacking in the current literature. This study aims to create a mathematical formula that accurately predicts the presence or absence of CON based on the most salient clinical measures of optic neuropathy. METHODS: A retrospective case series compares 108 patients (216 orbits) with either unilateral or bilateral TED-CON and 41 age-matched patients (82 orbits) with noncompressive TED. Utilizing clinical variables assessing optic nerve function and/or risk of compressive disease, and with the aid of generalized linear regression modeling, the authors create a mathematical formula that weighs the relative contribution of each clinical variable in the overall prediction of CON. RESULTS: Data from 213 orbits in 110 patients derived the formula: y = -0.69 + 2.58 × (afferent pupillary defect) - 0.31 × (summed limitation of ductions) - 0.2 × (mean deviation on Humphrey visual field testing) - 0.02 × (% color plates). This accurately predicted the presence of CON (y > 0) versus non-CON (y < 0) in 82% of cases with 83% sensitivity and 81% specificity. When there was no relative afferent pupillary defect, which was the case in 63% of CON orbits, the formula correctly predicted CON in 78% of orbits with 73% sensitivity and 83% specificity. CONCLUSIONS: The authors developed a mathematical formula, the Columbia TED-CON Diagnostic Formula (CTD Formula), that can help guide clinicians in accurately diagnosing TED-CON, particularly in the presence of bilateral disease and when no relative afferent pupillary defect is present.

Greater Proptosis Is Not Associated With Improved Compressive Optic Neuropathy in Thyroid Eye Disease.

PURPOSE: Despite the paucity of supporting data, it has generally been held that proptosis in thyroid eye disease (TED) may provide relative protection from compressive optic neuropathy (CON) by producing spontaneous decompression. The objective of this study was to investigate this phenomenon in patients with bilateral TED-CON. METHODS: We retrospectively reviewed the charts of 67 patients (134 orbits) with bilateral TED-CON at Columbia-Presbyterian Medical Center. Significant asymmetric proptosis (Hertel) was defined as ≥ 2 mm. Significant asymmetric CON was defined first, as the presence of an relative afferent pupillary defect. Those without an relative afferent pupillary defect were evaluated according to the TED-CON formula y = -0.69 - 0.31 × (motility) - 0.2 × (mean deviation) - 0.02 × (color vision) as previously established for the diagnosis of TED-CON. A difference in the formula result ≥ 1.0 between eyes was considered significant. Patients were then divided into 4 groups. RESULTS: Forty-one of 67 patients demonstrated asymmetric CON (29 by relative afferent pupillary defect, 12 by formula). Twenty-one of 67 patients demonstrated asymmetric proptosis. Only 5 of 12 (41.6%) of the patients who had both asymmetric proptosis and asymmetric CON (group 1) showed greater proptosis in the eye with less CON. Twenty-nine patients (group 2) showed that asymmetric CON occurred despite symmetrical proptosis. Seventeen patients (group 3), showed the inverse, that asymmetric differences in proptosis occurred with symmetrical CON. CONCLUSION: Despite commonly held assumptions, our results suggest that greater proptosis is not associated with improved TED-CON. Combining groups 1 to 3-all of which demonstrated asymmetry of either proptosis, CON, or both-91.4% of patients did not show a relationship between greater proptosis and improved CON.

Low-Flow Orbital Venous Malformation Masquerading as Rhabdomyosarcoma.

A 15-month-old male was referred for biopsy of presumed rhabdomyosarcoma in the setting of rapidly progressing left-sided proptosis. Examination revealed left periorbital edema and left hypoglobus. MRI revealed a soft-tissue density mass within the left lateral retrobulbar space. Several days later, he developed acute periorbital ecchymosis and increasing edema. With high suspicion for a vascular lesion, a CT scan was performed with dynamic arterial and venous imaging. Central filling was noted in the lateral retrobulbar component with increased enhancement on delayed venous imaging in the middle cranial fossa component favoring the diagnosis of a low-flow orbital venous malformation. In the setting of spontaneous orbital hemorrhage and risk of future vision loss, the decision was made to proceed with a combined neurosurgical approach treating the intracranial component and debulking the orbital component. This case highlights the importance of thorough radiographic evaluation prior to proceeding with a surgical procedure in the appropriate clinical context.

Utility of PROSE Device in the Management of Complex Oculoplastic Pathology.

PURPOSE: To describe the use of Prosthetic Replacement of the Ocular Surface Ecosystem (PROSE) device in the management of complex oculoplastic pathology. METHODS: The authors retrospectively reviewed the records of individuals over 18 years of age who were referred and successfully fit with the PROSE scleral device between January 1995 and June 2015. RESULTS: Nine cases were identified that had complex oculoplastic disease and severe corneal surface disease. All patients with ptosis had improvement in marginal reflex distance-1 following PROSE and 5 of 7 patients with ptosis were spared further surgical intervention. Two underwent surgical repair with successful corneal stabilization with PROSE. Those with eyelid malposition including ectropion, entropion, or trichiasis experienced improvement in their corneal surface and deferred further surgical intervention. CONCLUSIONS: These cases highlight the use of the PROSE device to elevate the upper eyelid in patients with lagophthalmos and ptosis, stabilize the corneal surface to allow for additional eyelid surgery to be performed safely, and protect the corneal surface in patients with intractable trichiasis and entropion. Prosthetic Replacement of the Ocular Surface Ecosystem should be considered in patients with complex oculoplastic pathology to improve visual function, corneal surface disease, and eyelid position.

Pituitary Adenoma Apoplexy of the Orbit, Diagnosis, and Management With Presurgical Embolization.

Orbital invasion of pituitary adenomas has been previously reported. In this report, the authors describe a 71-year-old female with a prolactinoma that presented with invasion of and apoplexy within the orbit. The patient underwent exenteration, followed by rapid tumor recurrence and growth. Given the hemorrhagic nature of the tumor, she subsequently underwent preoperative embolization and surgical resection. This case is notable in that it illustrates both apoplexy of a pituitary tumor within the orbit and the benefit of presurgical embolization.

IgG4-related orbital disease masquerading as thyroid eye disease, vice versa, or both?

A 40 year-old male presented after one year of unilateral, progressive, steroid-responsive, orbital inflammatory disease causing proptosis, extraocular muscle (EOM) restriction, and compressive optic neuropathy. The development of anti-thyroidal antibodies prompted the diagnosis of thyroid eye disease (TED); however, the prolonged active phase, remarkable reversibility of ophthalmic features with high-dose corticosteroids, unilaterally of disease, uncharacteristic EOM involvement (including both obliques), and the absence of autoimmune thyroid disease provoked consideration of alternative diagnoses. Inferior oblique biopsy stained positive for IgG4 with histologic features atypical of TED. The patient received rituximab for presumed IgG4-related orbital disease (IgG4-ROD) with subsequent reversal of compressive optic neuropathy, near complete resolution of EOM restriction, and improved proptosis, the latter two of which are not routinely anticipated in advanced TED. The possible role for B-cell depletion in both TED and IgG4-ROD suggests a degree of overlap in the underlying immune-related pathophysiology that is yet to be defined.