Disease Modulation Versus Modification: A Call for Revised Outcome Metrics in the Treatment of Thyroid Eye Disease.

PURPOSE: This perspective introduces the concepts of disease-modulating and -modifying therapy for thyroid eye disease and offers novel metrics for therapeutic outcomes. METHODS: A focused literature review was performed. RESULTS: Modulators are treatments that suppress disease symptoms whereas modifiers alter the natural history of a disease. Though many drugs are capable of exhibiting both effects, consideration of a drug's primary effect is useful when considering therapeutic options. For thyroid eye disease, corticosteroids and teprotumumab are effective at modulating many signs and symptoms of the disease, particularly those related to soft tissue inflammation. Orbital radiotherapy and rituximab have demonstrated effectiveness at durably modifying the natural history of thyroid eye disease. CONCLUSIONS: Outcome metrics should reflect the unique therapeutic objectives associated with disease modulation and modification. This conceptual framework should guide treatment of thyroid eye disease.

Invasive Squamous Cell Carcinoma Arising From a Cystic Brow Mass.

An 82-year-old woman presented with a 6-month history of an enlarging brow mass that developed after trauma. Clinical and MRI appearance of the lesion appeared consistent with epidermal inclusion cyst. However, excisional biopsy demonstrated invasive squamous cell carcinoma, which recurred 6 weeks later and required repeat surgical excision. To our knowledge, this represents the first case of squamous cell carcinoma arising from a posttraumatic epidermal inclusion cyst.

Residual Apical Lamina Papyracea as a Cause for Persistent Dysthyroid Optic Neuropathy After Orbital Decompression.

Two patients had persistent compressive dysthyroid optic neuropathy after decompression of the medial orbital wall and floor. In both cases, there was ~3 mm of unresected lamina papyracea anterior to the Annulus of Zinn, and removal of this residual bone led to resolution of the neuropathy. These illustrative cases suggest that, in some patients, even small amounts of residual crowding at the orbital apex can critically embarrass optic nerve perfusion, with resulting continued ischemic optic neuropathy.

Medical Accuracy of Patient Discussions in Oculoplastic Surgery on Social Media.

PURPOSE: The aim of this study was to characterize major topics of discussion in oculoplastic surgery on a social media forum and to evaluate the medical accuracy of the content discussed on these platforms. METHODS: A cross-sectional analysis of oculoplastics key search terms was performed on 2 active forums (r/PlasticSurgery and r/CosmeticSurgery) on Reddit. The content analysis involved the top posts in Reddit's history from 2008 to 2022. Medical accuracy was determined by actively practicing, board-certified, and fellowship-trained oculoplastic surgeons. RESULTS: The most common topics of patient discussions involved inquiring for advice regarding a procedure (44%) and sharing before-and-after photos (34%). The most common topics of patient discussions included providing support, encouragement, or sympathy for a patient (80%) and the cost of a procedure (62%). Misunderstanding of the medical pathophysiology of the patient's condition was seen in 68% of discussions on this social media platform. Medically inaccurate information was seen in 31% of all analyzed statements. When the type of physician performing a given procedure was disclosed, half reported an oculoplastic surgeon performed the surgery. CONCLUSIONS: The social media platform, Reddit, is a popular source of advice and information for current and prospective oculoplastic surgery patients. Such social media forums should be used as a sort of psychosocial and psychological support rather than as a primary source of medical information.

Congenital Orbital Fibrosis With Spontaneous Regression of Orbital Tumor.

Congenital orbital fibrosis (COF) is a rare disorder characterized by an infiltrating orbital mass with secondary involvement of the extraocular muscles that may present with extraocular muscle dysfunction, and globe and eyelid abnormalities in infancy. This condition is thought to be a nonprogressive process and literature on longitudinal assessment of COF is limited. The authors describe a case of COF which was followed for 15 years. The patient had stable symptoms of ocular dysmotility and ptosis but was noted to have spontaneous regression of the orbital mass on serial MRI.

Spheno-Orbital Meningioma - Treatment Outcomes and Factors Influencing Recurrence.

PURPOSE: To determine treatment outcomes, recurrence rates, and predictors of recurrence, to inform future therapeutic approaches for spheno-orbital meningiomas (SOM). METHODS: A retrospective single-center study of SOM treated from 1990 to 2021 was conducted with comprehensive neuro-ophthalmologic follow-up at Columbia University Medical Center (CUMC). Recurrence requiring reintervention was defined clinically as worsening of visual acuity, visual field defect, or ocular motility after an initial period of stabilization or 6 months of improvement following treatment, or radiologically as either a regrowth with an increase in tumor size by 20% at the site of previous growth or a new region of tumor growth. RESULTS: In total 46 patients met the inclusion criteria. The mean follow-up was 106 months (range 1-303). Dictated by the phenotype of the disease, patients underwent either gross- (50%), near- (17%), or subtotal resection (26%). Removal of the anterior clinoid process (ACP) was performed in 52% of patients. Nine patients (20%) required an enucleation or exenteration. Radiotherapy was employed at some point of treatment in 50% of cases. Inherited cases (24%) were referred to CUMC for treatment following 1 or more recurrences. The total recurrence rate, including inherited cases, was 54%, occurring at a mean interval of 43 months. The recurrence rate of patients treated solely at CUMC was 40%, occurring at a mean interval of 41 months. A subset of patients (32%) had 2 or more recurrences. Histopathology at the first surgery was WHO grade I (87%) and II (13%) and at the final surgery was WHO grade I (74%), II (21%), and III (4%). A subset of grade I tumors that received radiotherapy (35%) evolved to a higher grade or developed multiple recurrences without a change in histologic grade I. Grade II tumors and treatment with radiotherapy increased the odds of recurrence. Removal of the ACP and gross total resection decreased the odds of recurrence. CONCLUSION: Due to the routinely long interval to tumor recurrence, lifelong surveillance of patients with SOM is prudent. ACP resection and gross total resection, where possible, reduce tumor recurrence and the need for further treatment. Radiotherapy should be reserved for higher-grade meningiomas and select grade I tumors.

Association of Patient Age and the Thyroid Eye Disease-Clinical Activity Score.

PURPOSE: To investigate the association between age and clinical activity score (CAS) in patients with active, untreated thyroid eye disease. METHODS: A retrospective review was conducted of patients with active, untreated thyroid eye disease at a single institution between 2010 and 2020 whose ophthalmologic symptoms began no more than 9 months prior to the initial visit. Exclusion criteria included surgical or systemic thyroid eye disease treatment before or during the study period. Demographic and clinical data were collected for all patients, including a 7-point CAS at visit 1 (CAS1) and a 10-point score at visit 2 (CAS2). Patients were stratified by age: Group 1 (18-45), Group 2 (46-70), and Group 3 (71-85). RESULTS: A total of 156 patients were included: mean age 51.7 ± 15.8 years, 79.5% female. CAS1 differed significantly across groups: 1.9 ± 1.0 (Group 1), 2.7 ± 1.4 (Group 2), and 2.2 ± 1.6 (Group 3), p = 0.005. Findings were similar for CAS2: 2.2 ± 1.4 (Group 1), 3.0 ± 1.8 (Group 2), and 2.8 ± 1.9 (Group 3), p = 0.030. Post hoc analysis showed a statistically significant difference between Groups 1 and 2 (p = 0.004, visit 1; p = 0.025, visit 2) but not between other pairs. Patients with CAS1 of 0-3 (n = 129) were younger on average than those with CAS1 4-7 (n = 27): 50.4 ± 16.2 versus 58.2 ± 12.8 years (p = 0.009). Conjunctival redness (p = 0.019) and chemosis (p ≤ 0.001) were more common in older patients at both visits. CONCLUSIONS: Patients aged 46-70 years with active, untreated thyroid eye disease had significantly higher CAS1 and CAS2 than younger patients in this study, largely driven by differences in conjunctival redness and chemosis.

Inflammation and Fibrosis in Orbital Inflammatory Disease: A Histopathologic Analysis.

PURPOSE: The purpose of this study was to compare the histopathologic inflammation and fibrosis of orbital adipose tissue in orbital inflammatory disease (OID) specimens. METHODS: In this retrospective cohort study, inflammation, and fibrosis in orbital adipose tissue from patients with thyroid-associated orbitopathy (TAO), granulomatosis with polyangiitis (GPA), sarcoidosis, nonspecific orbital inflammation (NSOI), and healthy controls were scored by 2 masked ocular pathologists. Both categories were scored on a scale of 0 to 3 with scoring criteria based on the percentage of specimens containing inflammation or fibrosis, respectively. Tissue specimens were collected from oculoplastic surgeons at 8 international centers representing 4 countries. Seventy-four specimens were included: 25 with TAO, 6 with orbital GPA, 7 with orbital sarcoidosis, 24 with NSOI, and 12 healthy controls. RESULTS: The mean inflammation and fibrosis scores for healthy controls were 0.0 and 1.1, respectively. Orbital inflammatory disease groups' inflammation (I) and fibrosis (F) scores, formatted [I, F] with respective p -values when compared to controls, were: TAO [0.2, 1.4] ( p = 1, 1), GPA [1.9, 2.6] ( p = 0.003, 0.009), sarcoidosis [2.4, 1.9] ( p = 0.001, 0.023), and NSOI [1.3, 1.8] ( p ≤ 0.001, 0.018). Sarcoidosis had the highest mean inflammation score. The pairwise analysis demonstrated that sarcoidosis had a significantly higher mean inflammation score than NSOI ( p = 0.036) and TAO ( p < 0.0001), but no difference when compared to GPA. GPA had the highest mean fibrosis score, with pairwise analysis demonstrating a significantly higher mean fibrosis score than TAO ( p = 0.048). CONCLUSIONS: Mean inflammation and fibrosis scores in TAO orbital adipose tissue samples did not differ from healthy controls. In contrast, the more "intense" inflammatory diseases such as GPA, sarcoidosis, and NSOI did demonstrate higher histopathologic inflammation and fibrosis. This has implications in prognosis, therapeutic selection, and response monitoring in orbital inflammatory disease.

Spontaneous regression of a presumed orbital apex cavernous venous malformation.

A 42-year-old non-menopausal, non-pregnant woman presented with an incidentally noted right orbital apex lesion producing mild compressive optic neuropathy. Imaging revealed an apical, intraconal, inhomogenously enhancing mass consistent with a cavernous venous malformation displacing the optic nerve. The patient was monitored over a 15-year period with serial orbital imaging and clinical examinations and ultimately demonstrated significant regression in the size of the lesion, accompanied by the complete resolution of optic neuropathy. She was non-menopausal when the regression was noted and remained non-pregnant throughout the follow-up period.

Evolution of asymmetric proptosis during the active phase of thyroid eye disease.

PURPOSE: To assess the evolution of proptosis asymmetry during the active phase of bilateral thyroid eye disease (TED). METHODS: A retrospective study was conducted on patients with bilateral, active TED. Patients were measured by a single observer, using Hertel exophthalmometry from the time of initial presentation, during the active phase of TED, to the stable phase, 24-months later. Asymmetric proptosis was defined as a >2 mm intra-orbital difference in Hertel measurements. RESULTS: Fifty-one patients were enrolled. Patients presented at a mean time of 1.1 ± 2.9 months following the onset of TED symptoms. Stability of TED was established at 15.7 ± 12.3 months. At initial presentation, 41% of patients demonstrated asymmetric proptosis. Upon reaching the stable phase, asymmetric proptosis persisted in only 22% of patients. A decline in the rate asymmetric proptosis was greatest within the first 3 months of the active phase. CONCLUSIONS: Asymmetric proptosis is common in the setting of early active TED and decreases by 50% when the stable phase is reached. Therefore, diagnostic imaging is not routinely required to exclude alternative pathology in the cases of asymmetric TED. Perhaps more importantly, this finding supports the surgical paradigm of stable phase, graded orbital decompression, performed when the ultimate globe positions are achieved to avoid late postoperative asymmetry, resulting from the unanticipated evolution of proptosis when surgery is performed during the active phase of TED.

GNA11 Mutation in an Intracranial Melanocytoma with Orbital Involvement and Nevus of Ota.

The prognostic value of mutations in G-protein genes GNAQ and GNA11 in patients with intracranial and orbital melanocytomas is unknown. The authors present a case of GNA11 mutation (GNA11Q209L) in a 32-year-old male suffering from a meningeal melanocytoma with orbital involvement and ipsilateral Nevus of Ota. The patient underwent gamma knife stereotactic radiosurgery without biopsy and later partial transcranial resection of the melanocytic tumor that was subject to immunohistochemical and molecular analysis. A 50-gene next-generation sequencing panel revealed a 626A>T mutation in the GNA11 gene. One year later, intracranial extension of the melanocytoma necessitated a ventriculoperitoneal shunt and immunotherapy. Future work is needed to determine how GNA11 mutations in melanocytomas influence prognosis and monitoring strategies.

The Arched Rainbow Brow in Thyroid Eye Disease.

PURPOSE: To morphologically describe and mathematically quantify a novel clinical feature of thyroid eye disease (TED). METHODS: A retrospective study was conducted of TED patients and age-sex-matched normal controls. The arched Rainbow Brow appearance in TED patients was determined by unanimous agreement of 3 oculoplastic surgeons. Eyebrow curvature was assessed by plotting 15 points along the eyebrow in ImageJ. The fourth-degree polynomial ( y = ax4 + bx3 + cx2 + dx + e ) was fitted to each eyebrow. RESULTS: Two hundred seventy-one eyes were analyzed (200 TED and 71 age-sex-matched normal controls). A Rainbow Brow was identified in 42% of TED patients. A unilateral Rainbow Brow was seen in 15% of patients. The fourth-degree polynomial coefficients yielded significant differences between Rainbow Brow patients and age-sex-matched normal controls for the coefficients a, b, c , and d . Similar analysis of TED patients with and without a Rainbow Brow showed differences in coefficients a and b . Age >50 years ( p = 0.009) and the presence of brow fat expansion ( p < 0.001) were associated with the presence of a Rainbow Brow. Proptosis >24 mm showed a trend toward association with the presence of a Rainbow Brow ( p = 0.057). When considering the contribution of these features in a multivariable analysis, only brow fat expansion was a significant contributing factor ( p = 0.009). CONCLUSIONS: The Rainbow Brow is a distinct entity in TED and is likely consequent to brow fat pad expansion. Patients with a Rainbow Brow have different eyebrow curvature as compared to both normal age-sex-matched controls and TED patients without a Rainbow Brow.

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.

Predictive Modeling of New-Onset Postoperative Diplopia Following Orbital Decompression for Thyroid Eye Disease.

PURPOSE: To identify risk factors for the development of new-onset, postoperative diplopia following orbital decompression surgery based on patient demographics, clinical exam characteristics, radiographic parameters, and surgical techniques. METHODS: We conducted a multi-center retrospective chart review of patients who underwent orbital decompression for thyroid eye disease (TED). Patient demographics, including age, gender, smoking history, preoperative exophthalmometry, clinical activity score (CAS), use of peribulbar and/or systemic steroids, and type of orbital decompression were reviewed. Postoperative diplopia was determined at a minimum of 3 months postoperatively and before any further surgeries. Cross-sectional area ratios of each extraocular muscle to orbit and total fat to orbit were calculated from coronal imaging in a standard fashion. All measurements were carried out using PACS imaging software. Multivariable logistic regression modeling was performed using Stata 14.2 (StataCorp, College Station, TX). RESULTS: A total of 331 patients without preoperative diplopia were identified. At 3 months postoperatively, 249 patients had no diplopia whereas 82 patients developed diplopia. The average postoperative follow-up was 22 months (range 3-156) months. Significant preoperative clinical risk factors for postoperative diplopia included older age at surgery, proptosis, use of peribulbar or systemic steroids, elevated clinical activity score, and presence of preoperative compressive optic neuropathy. Imaging findings of enlarged cross-sectional areas of each rectus muscle to the overall orbital area also conferred a significant risk of postoperative diplopia. Regarding surgical factors, postoperative diplopia was more common among those undergoing medial wall decompression, bilateral orbital surgery, and balanced decompression, whereas endoscopic medial wall decompression was found to be relatively protective. CONCLUSIONS: This study identifies risk factors associated with the development of diplopia following orbital decompression using multivariable data. This study demonstrates that several characteristics including age, clinical activity score, the cross-sectional muscle to orbit ratios, in addition to the type of orbital decompression surgery, are predictive factors for the development of new-onset postoperative diplopia.

Mathematical Modeling of Eyebrow Curvature.

The aim of the study is to describe a mathematical model for analyzing eyebrow curvature that can be applied broadly to curvilinear facial features. A total of 100 digital images (50 men, 50 women) were obtained from standardized headshots of medical professionals. Images were analyzed in ImageJ by plotting either 8 or 15 points along the inferior-most row of contiguous brow cilia. A best-fit curve was automatically fit to these points in Microsoft Excel. The second derivative of the second-degree polynomial and a fourth-degree polynomial were used to evaluate brow curvature. Both techniques were subsequently compared with each other. A second-degree polynomial and fourth-degree polynomial were fit to all eyebrows. Plotting 15 points yielded greater goodness-of-fit than plotting 8 points along the inferior brow and allowed for more sensitive measurement of curvature across all images. A fourth-degree polynomial function provided a closer fit to the eyebrow than a second-degree polynomial function. This method provides a simple and reliable tool for quantitative analysis of eyebrow curvature from images. Fifteen-point plots and a fourth-degree polynomial curve provide a greater goodness-of-fit. The authors believe the described technique can be applied to other curvilinear facial features and will facilitate the analysis of standardized images.

Thrombosed orbital arteriovenous malformation in a patient with lymphangioleiomyomatosis.

A 47 year-old female with lymphangioleiomyomatosis developed right periorbital pain worsened while chewing, six months prior. Neuroimaging demonstrated a heterogenous inferotemporal right orbital mass extending through the inferior orbital fissure into the temporalis fossa, with flow voids. Given the patient's past medical history, the lesion was presumed to be a perivascular epithelioid cell tumor, a manifestation of lymphangioleiomyomatosis. A lateral orbitotomy revealed a well-circumscribed bluish-red lesion with areas of hemorrhage that was resected in total. Histopathology, however, was consistent with a thrombosed orbital arteriovenous malformation likely arising from the zygomaticotemporal neurovascular bundle. Lymphangioleiomyomatosis is a rare progressive disease that causes cystic destruction of the lungs and is frequently associated with extrapulmonary tumor infiltration, typically of the kidney and liver. Lymphangiomyoleiomyomatosis cell pathogenesis includes a pro-angiogenic micro-environment, classically expressing vascular endothelial factor-C and -D, which we postulate may have contributed to the development of the orbital arteriovenous malformation.

Atypical presentation of invasive myoepithelioma in a pediatric patient.

A 15-year-old girl presented with a mobile lesion with yellowish hue on the posterior lamella of the right lower eyelid adjacent to the punctum. Four years prior, a lesion thought to be a chalazion was excised from the same location. There was subsequent progressive painless enlargement. The patient ultimately underwent an internal excision of the mass. Histopathology demonstrated infiltrative nests and cords of epithelioid and plasmacytoid cells with abundant eosinophilic myxoid-collagenous stroma along with focal infiltration of skeletal muscle with immunohistochemical staining consistent with an invasive myoepithelioma of mixed-cell type. Given concern for invasive disease, the patient underwent subsequent Mohs resection resulting in a 25% full thickness eyelid defect, which was repaired with direct closure of the wedge defect. There has been no recurrence of the disease for 7 months since the Mohs resection. This case illustrates the atypical presentation of an invasive myoepithelioma of the eyelid in a pediatric patient.

An elusive case of malignant optic nerve glioma with a suprasellar mass.

A 67-year-old man with multiple comorbidities presented with 3 weeks of orbital pain, proptosis, and no light perception vision in the left eye. Examination was notable for a left orbital apex syndrome with CN III, VI palsies, an optic neuropathy, and central retinal vein occlusion. Magnetic resonance imaging of the orbits was notable for extensive enhancement, enlargement, and T2 hyperintensity of the optic nerve, with perineural sheath enhancement, and chiasmal hyperintensity. Inflammatory workup and lumbar puncture were unremarkable. No improvement was seen after a 3-day course of intravenous solumedrol. Initial optic nerve biopsy revealed necrotic nerve tissue, macrophage infiltration, increased vascularization, and peripheral gliosis. The volume of tissue was inadequate for genomic analysis. The patient was lost to follow-up but returned 5 months later with right-sided vision loss. Repeat neuroimaging showed a new suprasellar mass and progressive expansion and enhancement of both optic nerves. Biopsies of the suprasellar mass and left nerve at this time were consistent with a high-grade glial neoplasm, WHO grade IV. This is a rare case of glioblastoma involving the optic nerves and suprasellar region. In such cases, molecular profiling can improve diagnosis and may provide for targeted treatments in the future.

Orbital Lipofibromatosis in a Pediatric Patient.

A 10-month-old boy presented with a 3-month history of progressive left lower eyelid swelling. Examination demonstrated left lower eyelid fullness and hyperglobus with a fatty appearing inferior fornix mass. Imaging showed a mass isointense to fat in the left lower eyelid extending posteriorly, surrounding the inferior oblique with complete fatty infiltration, obscuration of the inferior rectus, and adherence to the globe. The patient underwent orbitotomy with biopsy and debulking of the tumor. Surgical pathology showed multiple fragments of adipose tissue with foci of plump and spindle-shaped cells arranged in bundles and fascicles, consistent with lipofibromatosis. This case illustrates a rare presentation of orbital lipofibromatosis in a pediatric patient.

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.