Teprotumumab for the Treatment of Recalcitrant Thyroid Eye Disease.

PURPOSE: Teprotumumab, an insulin-like growth factor 1 receptor monoclonal antibody, is FDA-approved to treat thyroid eye disease (TED). The initial clinical trials excluded patients with previous orbital irradiation, surgery, glucocorticoid use (cumulative dose >1 gm), or prior biologic treatment. Information on the use of teprotumumab for patients who failed prior therapy is limited. Our purpose is to characterize the efficacy of teprotumumab for the treatment of recalcitrant TED. METHODS: This is a multicenter retrospective study of all patients treated with teprotumumab for moderate-to-severe TED after failing conventional therapy with corticosteroids, orbital radiation, surgical decompression, biologics, or other steroid-sparing medications. Treatment failure was defined as an incomplete response to or reactivation after previous treatment. Only patients who received at least 4 infusions of teprotumumab were included in the analysis. Primary outcome measures comprised proptosis response (≥2 mm reduction in the study eye without a similar increase in the other eye), clinical activity score (CAS) response (≥2-point reduction in CAS), and diplopia response (≥1 point improvement in Gorman diplopia score in patients with baseline diplopia) following treatment. Adverse events and risk factors for recalcitrant disease were also evaluated. RESULTS: Sixty-six patients were included in this study, 46 females and 20 males. Average age was 59.3 years (range 29-93). The mean duration of disease from TED diagnosis to first infusion was 57.8 months. The proptosis, CAS, and diplopia responses in this recalcitrant patient population were 85.9%, 93.8%, and 69.1%, respectively. Patients experienced a mean reduction in proptosis of 3.1 ± 2.4 mm and a mean improvement in CAS of 3.8 ± 1.6. Patients who underwent prior decompression surgery experienced a statistically significant decrease in diplopia response (46.7% vs. 77.5%, p = 0.014) and proptosis response (75.0% vs. 90.9%, p = 0.045) when compared with nondecompression patients. Additionally, there were no significant differences in proptosis, CAS, and diplopia responses between patients with acute (defined as disease duration <1 year) versus chronic (disease duration ≥1 year) TED. While most adverse events were mild to moderate, 4 patients reported serious adverse events related to persistent hearing loss. CONCLUSIONS: Patients with recalcitrant TED demonstrated a significant improvement after teprotumumab in each of the primary study outcomes. The degree of proptosis reduction, diplopia response, and CAS improvement in the recalcitrant group were similar to those of treatment-naïve patients from the pivotal clinical trials. Patients with a prior history of orbital decompression, however, demonstrated poor improvement in diplopia and less reduction in proptosis than surgery naïve patients. These results indicate that teprotumumab is a treatment option for the treatment of patients with TED recalcitrant to prior medical therapies.

Subcutaneous tocilizumab for active thyroid eye disease refractory to orbital radiation and systemic steroids in tobacco smokers.

PURPOSE: Tocilizumab (TCZ) through intravenous infusion has been shown to effectively treat active thyroid eye disease (TED) refractory to systemic steroids. TCZ is also available as a self-administered subcutaneous injection, but data demonstrating the efficacy of this formulation are limited. This study investigated the efficacy and safety of subcutaneous TCZ (SC-TCZ) for the treatment of active, moderate-to-severe TED in smokers. MATERIALS AND METHODS: This retrospective clinical case series evaluated the clinical outcomes and adverse effects of SC-TCZ when taken for a minimum of 4 months by patients with moderate-to-severe TED and a current or recent history of cigarette smoking. RESULTS: Three patients received SC-TCZ every 1-2 weeks (4.6-11.2 mg/kg/month). The average pre-to-posttreatment clinical activity score reduction was 5.4, and proptosis was reduced by an average of 2.0 mm. No serious adverse effects were reported. CONCLUSION: SC-TCZ may be a useful and effective therapy for treating challenging cases of inflammatory TED and offers a safe alternative to office or hospital-based infusions. Further studies are needed to better understand optimal dosing regimens and relative efficacy compared to monthly TCZ infusions and other immunotherapies.

Efficacy of lateral orbital rim decompression in patients with prior rim-sparing, three-wall orbital decompression.

PURPOSE: The purpose was to study the effects of removal of the lateral orbital rim in patients with prior three-wall decompression for thyroid eye disease (TED). MATERIALS AND METHODS: This was a single-institution retrospective case series of patients presenting with symptoms and signs of residual symptomatic proptosis that had previously undergone three-wall decompression for TED. Data collected included patient age, gender, presenting symptoms, ocular history, proptosis reduction, and complications. RESULTS: Eleven orbits were identified. The mean preoperative exophthalmometry for the operative eye was 24.0 mm with 2.7 mm of relative proptosis. Removal of the lateral orbital rim resulted in a mean reduction in proptosis of 2.5 mm (range: 0.5-5.0 mm, P < 0.001). There was no significant change in diplopia, lagophthalmos, margin reflex distance (MRD) 1, MRD2, or exposure keratopathy. No canthal deformities were noted. All subjects reported satisfaction with functional and cosmetic outcomes of lateral orbital rim removal, and none reported problems with external contour irregularities of the lateral canthal region. CONCLUSION: Removal of the lateral orbital rim as part of a maximal orbital bony decompression adds to the decompressive effect of proptosis reduction with minimal side effects.

Stereotactic navigation in orbital decompression surgery - Does it shorten operative time and improve outcomes?

PURPOSE: Stereotactic navigation is being increasingly used for orbital decompression (OD). Recent studies have cited clinical benefits of navigation including greater proptosis reduction but have differed regarding effects on operative time. This study aimed to evaluate navigated vs. non-navigated OD with respect to operative time and proptosis reduction. MATERIALS AND METHODS: Retrospective nonrandomized comparative trial of navigated vs. nonnavigated OD. Operative time and proptosis reduction were recorded and analyzed for all patients. RESULTS: A total of 30 orbital decompressions were included; 14 were performed with stereotactic navigation (SN), and 16 were performed without SN. On average, the SN group took 19 minutes longer for 3-wall decompressions (p = 0.185), 25 minutes shorter for balanced decompressions (p = 0.025), and 18 minutes longer (p = 0.067) for lateral wall decompressions. Mean proptosis reduction (PR) in 3-wall decompressions was greater in the SN group (p = 0.02). Among balanced wall decompressions, mean PR was 4.25 mm and 3.67 mm for the SN and non-SN groups (p = 0.30), respectively. For lateral wall decompressions, mean PR was 2.63 mm with SN and 2.50 mm without SN (p = 0.45). CONCLUSIONS: This study showed no difference in operative times between navigated and non-navigated OD, although empirical experience showed variable times required for registration and intraoperative troubleshooting of the navigation system. This study also found that navigation increased proptosis reduction for all types of OD. Further randomized controlled trials are needed to better understand the impact of navigation technology on operative times and surgical outcomes.

Outcomes of corneal neurotisation using processed nerve allografts: a multicentre case series.

BACKGROUND: Corneal neurotisation is a rapidly evolving procedure treating neurotrophic keratopathy. The variety of surgical techniques used and corresponding outcomes after corneal neurotisation are not well understood. This study describes the techniques and outcomes in the largest case series of corneal neurotisation using processed nerve allografts to date. METHODS: This is a retrospective case series of patients who underwent corneal neurotisation with human cadaveric processed nerve allografts. All patients had preoperative and postoperative description of best corrected visual acuity and measurement of corneal sensation. Comparative studies after stratification of techniques were performed. RESULTS: A total of 17 patients were identified. The cause of corneal anaesthesia was prior infection in eight cases, trigeminal nerve palsy in eight cases and ocular trauma in one case. There were no intraoperative or postoperative complications. Following neurotisation surgery, the time to first gain of corneal sensation and maximal gain of sensation occurred at a mean of 3.7 months (range 1-8 months) and 6.6 months (range 3-15 months), respectively. The mean preoperative and postoperative corneal sensation as measured by Cochet-Bonnet aesthesiometry was 0.36 cm (range 0-3.2 cm) and 4.42 cm (range 0-6 cm), respectively (p<0.01). Visual acuity was unchanged after neurotisation. There were no statistical differences in outcomes based on end-to-end versus end-to-side coaptations, donor nerve selection or laterality of donor nerve. CONCLUSION: Corneal neurotisation with processed nerve allografts is a safe and effective procedure. This study provides further evidence for the use of processed nerve allografts for corneal neurotisation.

Orbital Hemorrhagic Necrosis, Globe Rupture, and Death From Intraorbital Injection of 1% Sodium Deoxycholate in a Murine Model.

PURPOSE: Deoxycholic acid (DCA) 1% is an injectable detergent indicated for submental fat reduction, although clinically it is being injected off-label for orbital fat prolapse. It is known to cause severe inflammation, local nerve dysfunction, and tissue necrosis, all of which could be catastrophic in the orbit and periocular region. This study evaluated the effects of periocular DCA on orbital and ocular adnexal tissues in a murine model. METHODS: Mice were treated via split-face intraorbital injections, subcutaneous injections, and topical cornea application with DCA versus phosphate-buffered saline. Whole heads were fixed, decalcified, and sectioned for orbital histology after 1-7 days. Matched pairs of human globes and mouse globes were immersed in either phosphate-buffered saline or 1% DCA for 72 hours. RESULTS: Six of 11 mice receiving intraorbital DCA injections died within minutes. Surviving mice developed severe orbital inflammatory necrosis. All orbits injected with phosphate-buffered saline were clinically and histologically normal. Six mice were treated with lower concentrations of DCA and all developed variable amounts of orbital inflammation, hemorrhage, and globe necrosis. Mice receiving subcutaneous DCA injection to the lower eyelid showed inflammatory necrosis, edema, and lid malposition. Topical application of DCA to mouse corneas caused no external or histologic changes. Human and mouse globes immersed ex vivo in DCA developed corneal edema and cataract formation without observable scleral changes. CONCLUSION: Intraorbital and periocular injection of DCA can cause devastating complications in a murine model, and significant caution is advised for off-label use in the periocular region.

Orbital Bony Reconstruction With Presized and Precontoured Porous Polyethylene-Titanium Implants.

PURPOSE: Complex bony orbital defects are reconstructively challenging due to loss of intraoperative anatomical landmarks and adjacent support. Presized and precontoured porous polyethylene-titanium implants (Medpor Titan 3D Orbital Floor Implant) are designed to reestablish normal orbital floor and medial wall anatomy and are modeled after anatomically averaged orbits. This is the first study to report clinical outcomes with this implant. METHODS: This retrospective case series reviewed clinical data and outcomes for patients undergoing orbital reconstruction with a presized and precontoured porous polyethylene-titanium orbital implant from January 2016 to June 2018. RESULTS: A total of 34 orbits of 33 patients were identified (mean age: 43 ± 16 years, 70% men). Most bony defects were a result of trauma and included large orbital floor deformities (100%), medial wall defects (74%), disrupted inferomedial struts (68%), and broken posterior ledges (82%). Symptomatic diplopia (73%) and enophthalmos (89%, mean: 3.7 ± 2.1 mm) were common preoperatively. Many cases were revisions (44%). Mean follow up was 7.8 ± 6.7 months. All patients had improved globe positioning, enophthalmos, and hypoglobus. Seven patients had persistent postoperative diplopia: 6 responded to prism therapy and 1 required strabismus surgery. One patient required retrobulbar hematoma drainage and 1 patient required implant explantation due to chronic infection. CONCLUSIONS: Commercially available presized and precon toured porous polyethylene-titanium implants are useful for complex orbital bony defects and can achieve functional improve ments in diplopia, enophthalmos, and extraocular motility with a low incidence of postoperative complications or revisional surgery.

Bilateral Poorly Differentiated Adenocarcinoma of the Lacrimal Gland With Tumor Regression After Treatment With Pembrolizumab.

An 85-year-old man presented with a 6-month history of worsening left proptosis and painless ophthalmoplegia. Imaging revealed an extensive intraconal and extraconal tumor extending to the level of the optic foramen, as well as the scalp, cheek, and the nasal bridge. Incisional biopsy was consistent with lacrimal gland adenocarcinoma. The patient underwent a left orbital exenteration followed by immunotherapy with pembrolizumab. The treatment was stopped prematurely after 5 cycles due to development of autoimmune colitis. Four months later, the patient developed new contralateral disease in the right orbit and an incisional biopsy again showed lacrimal gland adenocarcinoma. Following the incisional biopsy, no further treatment was administered, but over the ensuing 6 months, there was dramatic spontaneous regression of the tumor both clinically and radiographically. At 28 months, the patient is still alive with relatively stable disease.

A Modified Hughes Flap for Correction of Refractory Cicatricial Lower Lid Retraction With Concomitant Ectropion.

INTRODUCTION: Correction of lower eyelid retraction commonly involves one or more techniques, including recession of the eyelid retractors, spacer grafts, horizontal lid tightening, and midface lifting. However, patients presenting with cicatricial lower lid retraction following prior eyelid surgery often have scarring and concomitant ectropion or entropion that cause unpredictable wound healing, recicatrization, and suboptimal outcomes. The modified Hughes tarsoconjunctival flap is typically used to repair full-thickness eyelid defects. Prior reports describe treating refractory lower lid retraction with a modified Hughes flap placed beneath the tarsus after full-thickness blepharotomy. We present our experience with a novel surgical technique for treating refractory cicatricial lower lid retraction using a modified Hughes flap above the tarsus after excision of the scarred lid margin. METHODS: Three patients were treated using this technique. The upper edge of the lower eyelid and associated scar tissue are excised. A modified Hughes flap is mobilized and secured above the posterior lamellar remnant. A full-thickness skin graft is placed over the flap. The flap is divided 4-5 weeks later. RESULTS: This surgical technique was employed in all 3 cases. All cases were revisional, with 2 having extensive multioperative histories with multiple unsuccessful reconstructions and lid retraction repairs. All patients had improvement in cicatricial eyelid retraction, lagophthalmos, exposure keratopathy, and resolution of concomitant cicatricial ectropion. CONCLUSIONS: The technique of using a modified Hughes flap to reconstruct above the tarsus with excision of the scarred lid margin was effective in correcting refractory cicatricial lower lid retraction. This procedure can be considered in multioperative cases in which traditional techniques for lower lid retraction repair have failed. Reconstructing a new lid margin reduces the risk of recicatrization and suboptimal results.

Orbital cholesterol granuloma: A report and discussion of orbital findings.

PURPOSE: To report a case of orbital cholesterol granuloma and discuss the orbital findings seen in this entity. OBSERVATION: A 38-year-old male presented with an 8-month history of progressive left upper lid ptosis and hypoglobus. Clinical examination was significant for 3 mm of hypoglobus and restricted supraduction in the left eye. Contrasted computed tomography imaging revealed a well-circumscribed lesion in the superotemporal orbit causing extensive bone erosion that appeared to arise from the lacrimal gland. An incisional biopsy was performed, and histopathological evaluation demonstrated fibrovascular tissue surrounding a mixture of histiocytes and cholesterol clefts, consistent with a cholesterol granuloma. CONCLUSIONS AND IMPORTANCE: Orbital cholesterol granulomas are rare lesions that are predominantly found in the superotemporal orbit. These lesions can be associated with marked bony changes in the superotemporal fossa that can be mistaken for a lacrimal gland neoplasm; however, bony erosion is a hallmark of this lesion and should be considered on the differential diagnosis of any lacrimal gland mass with extensive bony erosion.

Odontogenic choristoma presenting as dermolipoma.

A 5-year-old otherwise healthy girl presented to the oculoplastic service with a painless superotemporal subconjunctival mass in the left eye. Visual acuity was within normal limits, and there was no evidence of proptosis or orbital enlargement. Excision was performed to remove the anterior portion of the mass for alleviation of symptoms. On histopathological analysis, the mass was comprised of fibroadipose tissue consistent with dermolipoma and contained a hard nodule found to be a calcified tooth. In the periocular region, odontogenic choristoma (tooth) is a rare lesion, and has been reported to occur within teratomas, dermoid cysts, and displaced oral embryonic epithelium. We describe an unusual case of a tooth occurring within a sporadic dermolipoma. The clinical presentation, examination, management, and histopathology are reviewed.

Ocular Considerations in Face Transplantation: Report of 2 Cases and Review of the Literature.

PURPOSE: Periorbital injuries are common in face transplantation (FT) candidates. It is therefore essential that the ophthalmologist play a central role in the multidisciplinary treatment of these patients. In this study, the authors perform a comprehensive review of all procedures involving periorbital components, provide an update for the ophthalmology community regarding the current state of the field, and present 2 cases. METHODS: A comprehensive review of the literature for all FT procedures including periorbital components was performed. The authors also present 2 patients who received FT including periorbital components for extensive facial disfigurement. One patient sustained high-energy avulsive ballistic injury and underwent a total face, double jaw, and tongue transplant in 2012. The second patient received a total face, eyelids, ears, and skeletal subunits transplant for extensive facial burns in 2015. RESULTS: Literature review demonstrated that 22 (54%) of the 41 patients undergoing FT received allografts containing periorbital components. Only 14 cases (64%) reported on the presence of ocular and periocular complications. The most common complications consisted of lower eyelid ectropion and lagophthalmos, and nearly all required revisional procedures. Both patients presented with significant periorbital scarring and demonstrated good visual acuity and aesthetic outcomes at postoperative follow up between 6 and 28 months. CONCLUSIONS: Face transplantation can address extensive facial and periorbital disfigurement with satisfactory functional and aesthetic outcomes. The majority of FT performed to date have included periorbital components, and postoperative ocular and periocular complications are common. It is critical for ophthalmologists to play a central role in the care of these patients.

The Effect of Prostaglandin Analogue Bimatoprost on Thyroid-Associated Orbitopathy.

Purpose: We characterize the effect of bimatoprost on orbital adipose tissue in thyroid-associated orbitopathy (TAO) with clinicopathologic correlation. Methods: Orbital adipose-derived stem cells (OASCs) from types 1 and 2 TAO and control patients with and without exposure to 1 µm bimatoprost were examined via immunohistochemistry, RT-PCR, and Western blot for cell viability, migration capacity, lipid content, adipocyte morphology, mitochondrial content, and levels of adipogenic markers. A retrospective chart review was performed for clinicopathologic correlation. In mice, optical coherence tomography and pattern electroretinography were performed at baseline and at 1 month following a retrobulbar injection of bimatoprost, followed by orbital exenteration for histopathologic examination. Results: Types 1 and 2 TAO-derived cells had a significantly higher migration capacity and lipid content than those of healthy controls. With the addition of bimatoprost, types 1 and 2 TAO and control adipocytes exhibited a significant decrease in lipid content with morphologic transformation into smaller and multilocular lipid droplets, and an increase in mitochondrial load and UCP-1 expression consistent with an increase in brown adipose tissue turnover. Retrobulbar injection of bimatoprost in mice did not alter the gross morphology, retinal thickness, or ganglion cell function in vivo. Conclusions: Bimatoprost inhibits adipogenesis in OASCs and upregulates pathways involved in the browning of adipocytes. Furthermore, retrobulbar injection of bimatoprost is tolerated without immediate adverse effects in mice. Our results suggest a potential future application of prostaglandin analogues in the treatment of TAO.

Incidence of diplopia after division and reattachment of the inferior oblique muscle during orbital fracture repair.

BACKGROUND: Wide surgical access to the orbital floor and medial wall is often impaired by the course of the inferior oblique muscle. There is no current consensus on the optimal surgical approach for exposure, and techniques involving inferior oblique division are generally shunned for concern of possible complications. OBJECTIVE: To determine the safety and outcomes of inferior oblique division and reattachment for surgical access to the orbital floor and medial wall during orbital fracture repair. METHODS: Retrospective, single-center, review of 85 patients that underwent orbital floor, medial wall or combined fracture repair with division and reattachment of the inferior oblique near its origin. Measured characteristics include surgical approach, type of surgery, time to surgery, pre- and post-operative diplopia, enophthalmos, and complications. RESULTS: Forty-five patients (52.9%) with no pre-operative diplopia were followed up for a mean of six months. Of these, six patients (13.3%) developed post-operative binocular diplopia that resolved in all patients on an average of three months (range 2-6 months). No patients developed torsional diplopia. One patient developed a hematoma two years later attributable to capsular contraction around the implant. CONCLUSION: Division and reattachment of the inferior oblique muscle is a safe method that allows for panoramic surgical visualization of the inferior and medial orbit.

Transcriptome Analysis of Orbital Adipose Tissue in Active Thyroid Eye Disease Using Next Generation RNA Sequencing Technology.

OBJECTIVE: This study utilized Next Generation Sequencing (NGS) to identify differentially expressed transcripts in orbital adipose tissue from patients with active Thyroid Eye Disease (TED) versus healthy controls. METHOD: This prospective, case-control study enrolled three patients with severe, active thyroid eye disease undergoing orbital decompression, and three healthy controls undergoing routine eyelid surgery with removal of orbital fat. RNA Sequencing (RNA-Seq) was performed on freshly obtained orbital adipose tissue from study patients to analyze the transcriptome. Bioinformatics analysis was performed to determine pathways and processes enriched for the differential expression profile. Quantitative Reverse Transcriptase-Polymerase Chain Reaction (qRT-PCR) was performed to validate the differential expression of selected genes identified by RNA-Seq. RESULTS: RNA-Seq identified 328 differentially expressed genes associated with active thyroid eye disease, many of which were responsible for mediating inflammation, cytokine signaling, adipogenesis, IGF-1 signaling, and glycosaminoglycan binding. The IL-5 and chemokine signaling pathways were highly enriched, and very-low-density-lipoprotein receptor activity and statin medications were implicated as having a potential role in TED. CONCLUSION: This study is the first to use RNA-Seq technology to elucidate differential gene expression associated with active, severe TED. This study suggests a transcriptional basis for the role of statins in modulating differentially expressed genes that mediate the pathogenesis of thyroid eye disease. Furthermore, the identification of genes with altered levels of expression in active, severe TED may inform the molecular pathways central to this clinical phenotype and guide the development of novel therapeutic agents.