Thinking inside the box: Current insights into targeting orbital tissue remodeling and inflammation in thyroid eye disease.

Thyroid eye disease (TED) is an autoimmune disorder that manifests in the orbit. In TED, the connective tissue behind the eye becomes inflamed and remodels with increased fat accumulation and/or increased muscle and scar tissue. As orbital tissue expands, patients develop edema, exophthalmos, diplopia, and optic neuropathy. In severe cases vision loss may occur secondary to corneal scarring from exposure or optic nerve compression. Currently there is no cure for TED, and treatments are limited. A major breakthrough in TED therapy occurred with the FDA approval of teprotumumab, a monoclonal insulin-like growth factor 1 receptor (IGF1R) blocking antibody. Yet, teprotumumab therapy has limitations, including cost, infusion method of drug delivery, variable response, and relapse. We describe approaches to target orbital fibroblasts and the complex pathophysiology that underlies tissue remodeling and inflammation driving TED. Further advances in the elucidation of the mechanisms of TED may lead to prophylaxis based upon early biomarkers as well as lead to more convenient, less expensive therapies.

MicroRNA-130a Is Elevated in Thyroid Eye Disease and Increases Lipid Accumulation in Fibroblasts Through the Suppression of AMPK.

Purpose: Thyroid eye disease (TED) is a condition that causes the tissue behind the eye to become inflamed and can result in excessive fatty tissue accumulation in the orbit. Two subpopulations of fibroblasts reside in the orbit: those that highly express Thy1 (Thy1+) and those with little or no Thy1 (Thy1-). Thy1- orbital fibroblasts (OFs) are more prone to lipid accumulation than Thy1+ OFs. The purpose of this study was to investigate the mechanisms whereby Thy1- OFs more readily accumulate lipid. Methods: We screened Thy1+ and Thy1- OFs for differences in microRNA (miRNA) expression. The effects of increasing miR-130a levels in OFs was investigated by measuring lipid accumulation and visualizing lipid deposits. To determine if adenosine monophosphate-activated protein kinase (AMPK) is important for lipid accumulation, we performed small interfering RNA (siRNA)-mediated knockdown of AMPKß1. We measured AMPK expression and activity using immunoblotting for AMPK and AMPK target proteins. Results: We determined that miR-130a was upregulated in Thy1- OFs and that miR-130a targets two subunits of AMPK. Increasing miR-130a levels enhanced lipid accumulation and reduced expression of AMPKα and AMPKß in OFs. Depletion of AMPK also increased lipid accumulation. Activation of AMPK using AICAR attenuated lipid accumulation and increased phosphorylation of acetyl-CoA carboxylase (ACC) in OFs. Conclusions: These data suggest that when Thy1- OFs accumulate in TED, miR-130a levels increase, leading to a decrease in AMPK activity. Decreased AMPK activity promotes lipid accumulation in TED OFs, leading to excessive fatty tissue accumulation in the orbit.

The aryl hydrocarbon receptor pathway controls matrix metalloproteinase-1 and collagen levels in human orbital fibroblasts.

Thyroid eye disease (TED) affects 25-50% of patients with Graves' Disease. In TED, collagen accumulation leads to an expansion of the extracellular matrix (ECM) which causes destructive tissue remodeling. The purpose of this study was to investigate the therapeutic potential of activating the aryl hydrocarbon receptor (AHR) to limit ECM accumulation in vitro. The ability of AHR to control expression of matrix metalloproteinase-1 (MMP1) was analyzed. MMP1 degrades collagen to prevent excessive ECM. Human orbital fibroblasts (OFs) were treated with the pro-scarring cytokine, transforming growth factor beta (TGFß) to induce collagen production. The AHR ligand, 6-formylindolo[3,2b]carbazole (FICZ) was used to activate the AHR pathway in OFs. MMP1 protein and mRNA levels were analyzed by immunosorbent assay, Western blotting and quantitative PCR. MMP1 activity was detected using collagen zymography. AHR and its transcriptional binding partner, ARNT were depleted using siRNA to determine their role in activating expression of MMP1. FICZ induced MMP1 mRNA, protein expression and activity. MMP1 expression led to a reduction in collagen 1A1 levels. Furthermore, FICZ-induced MMP1 expression required both AHR and ARNT, demonstrating that the AHR-ARNT transcriptional complex is necessary for expression of MMP1 in OFs. These data show that activation of the AHR by FICZ increases MMP1 expression while leading to a decrease in collagen levels. Taken together, these studies suggest that AHR activation could be a promising target to block excessive collagen accumulation and destructive tissue remodeling that occurs in fibrotic diseases such as TED.

Dilated Superior Ophthalmic Vein: Clinical and Radiographic Features of 113 Cases.

PURPOSE: Dilated superior ophthalmic vein (SOV) is an uncommon radiographic finding. The authors review the presentation, etiology, radiography, and visual implications of 113 patients with dilated SOV. METHODS: An observational case series and multicenter retrospective chart review were conducted. There were 113 patients with a dilated SOV. Outcome measures included patient demographics, clinical features, radiographic findings, diagnosis, and treatment, and treatment outcomes were assessed. RESULTS: Cases included 75 women (66%) and 38 men (34%) with a mean age of 49 ± 24 years (range, 0.4-90 years). Diagnoses fell under 6 categories: vascular malformation (n = 92, 81%), venous thrombosis (n = 11, 10%), inflammatory (n = 6, 5%), traumatic hemorrhage (n = 2, 2%), lymphoproliferative (n = 1, 1%), and infectious (n = 1, 1%). Imaging modalities utilized included MRI (n = 98, 87%), digital subtraction angiography (n = 77, 68%), CT (n = 29, 26%), and ultrasonography (n = 4, 4%). Disease status at last follow up included no evidence of disease (n = 57, 50%), alive with persistent disease (n = 53, 47%), and expired from disease (n = 3, 3%). Treatment and management was tailored to the underlying disease process with a mean follow up of 18 months (range, 1 day to 180 months). Visual impairment observed at presentation and last follow up across all cases was 26% and 22%, respectively. CONCLUSION: Dilated SOV is a rare radiographic finding resulting from a wide spectrum of etiologies with clinical implications ranging from benign to sight- and life-threatening. Dilated SOV is most often found with dural-cavernous fistula or carotid-cavernous fistula, orbital or facial arteriovenous malformation, and venous thrombosis. Recognition of this finding and management of the underlying condition is critical.

Novel Technique of Percutaneous Fat Graft for Repair of Persistent Large Pseudomeningocele.

BACKGROUND: Pseudomeningocele is an uncommon but problematic complication in lumbar spine surgery. Initial conservative measures frequently are successful, but persistence requires additional management. The current surgical approach can involve a range of techniques, including blood patches, hydrogel/fibrin sealants, drains, open surgical repair of the dura, or a combination of the all techniques if symptoms persist. This report demonstrates a novel technique for repair via a percutaneous approach to deliver an autologous fat graft into the pseudomeningocele. CASE DESCRIPTION: A 64-year-old woman with a history of multiple complex lumbar spinal surgeries with previous durotomy had persistent positional headaches from an unresolved pseudomeningocele from L3 to L5. The defect and symptoms remained after all available surgical options were exhausted, including blood patches, hydrogel sealants (Duraseal), and open surgical repair with muscle and Gelfoam grafts. After autologous fat harvest, the patient underwent percutaneous repair of the pseudomeningocele with simultaneous aspiration of cerebrospinal fluid and injection of fat into the defect space. CONCLUSIONS: At 3 months postoperatively, the patient's symptoms were resolved with no clinical or radiographic findings of nerve root or thecal sac impingement and complete obliteration of the pseudomeningocele. This less-invasive approach offers the option of open surgical repair for persistent pseudomeningocele with the use of autologous graft material.

Keratoprosthesis in Ectodermal Dysplasia.

PURPOSE: To describe the complex surgical management and novel medical approach for a keratoprosthesis (KPro Boston type I) in a monocular, 73-year-old patient with ectodermal dysplasia and chronic, noninfectious corneal necrosis. METHODS: Best-corrected visual acuity (BCVA) was measured with Snellen letters. Surgical intervention included an amniotic membrane graft, complete replacement of the KPro, conjunctival flap graft, corneal donor tissue grafts combined with inferior rectus muscle advancement, periosteal tissue graft, tarso-conjunctival flap construction, and symblepharolysis. Infliximab was used as a medical adjunctive therapy. RESULTS: Initial KPro placement provided a BCVA of 20/25 and long-term stability. Subsequent chronic melting at the optic border necessitated numerous surgeries to prevent extrusion and failure. Ultimate fistulization was addressed with the formation of a surgical pocket. The addition of infliximab promoted ocular surface stability, and the patient has maintained a BCVA of 20/80. CONCLUSIONS: Ectodermal dysplasia can result in eyelid and corneal abnormalities, requiring a KPro for visual restoration. In the setting of chronic, sterile corneal melt, novel surgical approaches and the off-label use of infliximab allowed for visual rehabilitation.

Dacryocystitis As the Initial Presentation of Invasive Fungal Sinusitis in Immunocompromised Children.

Sino-orbital fungal infection is a rare, but life-threatening disease seen mainly in immunocompromised patients. While initial clinical impression may vary, dacryocystitis has rarely been described as the initial presenting sign. The authors present 2 pediatric cases of dacryocystitis as the initial sign of invasive fungal sinusitis. To their knowledge, this presenting sign has not been previously reported in the pediatric population. Management strategies and outcomes are discussed.

Biodegradable Fixation of the Orbital Rim After Lateral Orbitotomy.

PURPOSE: To describe authors' experience with repair of the lateral orbital rim with poly-L/DL-lactic acid (PDLLA) biodegradable plates using ultrasonic pin fixation after lateral orbitotomy with bone flap. METHODS: The authors retrospectively reviewed all patients who underwent a lateral orbitotomy with bone flap for biopsy of orbital tumors at their institution from January 2010 to May 2013. All patients underwent an orbitotomy by either a lateral eyelid crease incision or lateral canthotomy/cantholysis approach. A lateral bone flap was fashioned in the usual manner, extending from the frontozygomatic suture down the lateral rim for approximately 2 cm. The bone flap was repaired in each case with either a 6 or 7 hole PDLLA plate and secured with ultrasonic PDLLA pin fixation. RESULTS: Twenty-four patients were identified who underwent a lateral orbitotomy with bone flap. Of these patients, 10 were repaired with PDLLA plates. The average age of the patients with PDLLA bone flap fixation was 55 years (range 5-85). The average follow-up time was 12.9 months (range 4-42). Indications included 4 lacrimal gland tumors, 4 intraconal tumors, and 2 lateral orbital tumors. Final diagnosis included lymphoma (3), squamous cell carcinoma (1), neuroblastoma (1), amyloid (1), fibrous tissue (1), sarcoidosis (1), cavernous hemangioma (1), and idiopathic orbital inflammation (1). Three patients had edema of the surrounding soft tissues after surgery, all but 1 resolved by postop month 3. There were 2 cases of transient temporal numbness that resolved by postop month 1. There were no cases of vision loss, extraocular motility deficit, infection, or need for removal of the implant before absorption. CONCLUSIONS: PDLLA biodegradable plates with ultrasonic pin placement provide a safe, effective means for lateral rim fixation after orbitotomy with bone flap.

Conjunctivodacryocystorhinostomy and lacrimal sinus diversion via sinopsys surgical lacrimal stent: cadaveric proof of concept.

PURPOSE: To determine the viability of lacrimal sinus diversion by using a novel Sinopsys Surgical Lacrimal Stent. METHODS: Two disarticulated cadaveric heads were used in the laboratory. First, bilateral conjunctivodacryocystorhinostomies (CDCR) were performed by using a traditional Pyrex Jones tube and the Sinopsys Surgical Lacrimal Stent. The fluiditics were then evaluated by using contrast agent and fluroscopy. Subsequently, conjunctivoethmoidectomies (CE) and conjunctivomaxillectomies (CM) were performed by using the Sinopsys Surgical Lacrimal Stent, of which the fluiditics were also studied. RESULTS: The conjunctivodacryocystorhinostomy (CDCR) placement experience of the Jones tube and the Sinopsys Surgical Lacrimal Stent were similar. The CDCR fluiditics as measured by using contrast agent and fluoroscopy were identical with each draining 0.5 mL over 5 to 10 seconds. Placement of the Sinopsys Surgical Lacrimal Stent in the 4 ethmoid (CE) and 4 maxillary (CM) sinuses was similar to the CDCR experience. Fluiditics of lacrimal sinus diversion were similar to CDCR with drainage of 0.5 mL over 5 seconds. CONCLUSIONS: The Sinopsys Surgical Lacrimal Stent has flow characteristics that are similar to a Pyrex Jones tube. Drainage in the nose via a CDCR procedure is similar to drainage in the ethmoid and maxillary sinuses via a CE and CM, respectively.

Evaluation of levator function for efficacy of minimally invasive and standard techniques for involutional ptosis.

PURPOSE: To evaluate clinical and anatomic outcomes of surgery for involutional ptosis using standard-length or small incisions in relation to preoperative levator function. DESIGN: Retrospective study. METHODS: Sixty-three patients diagnosed with involutional ptosis who underwent surgical correction using a small or standard-length incision between November 2010 and December 2011 were reviewed; a single surgeon performed surgery using a small incision (8 to 10 mm) in 22 patients and a standard-length incision (20 to 22 mm) in 34 patients. All patients underwent standard preoperative ptosis evaluation with margin-to-reflex distance 1 and 2 measurements and levator function assessment. Patients were divided into 2 groups according to levator function (moderate: 5 to 10 mm; and good: >10 mm). Surgical success was evaluated based on the British Oculoplastic Surgery Society criteria. RESULTS: Of 83 upper eyelids of 63 patients, surgery was performed using a small incision in 40 and a standard incision in 43. In patients with good levator function, surgical success was achieved with a small incision in 18 eyelids (94.7%) and a standard incision in 20 eyelids (95.2%; P = .91). In patients with moderate levator function, surgical success was achieved with a small incision in 14 eyelids (66.7%) and with a standard incision in 18 eyelids (81.8%; P = .04). CONCLUSIONS: These findings indicate a similar surgical success rate in patients with good levator function, regardless of incision length. The surgical success rate in patients with moderate levator function was lower when using a small incision, perhaps because of decreased visualization and anatomic access.

American Society of Ophthalmic Plastic and Reconstructive Surgery fellowship survey: fellows selection criteria for training programs.

PURPOSE: To investigate the characteristics that American Society of Ophthalmic Plastic and Reconstructive Surgery fellows seek in fellowship training programs. METHODS: A 14-question anonymous SurveyMonkey survey was created for the 2011 to 2014 American Society of Ophthalmic Plastic and Reconstructive Surgery graduates. The survey evaluated fellow demographics, the interview process, and qualities fellows seek in fellowship training programs. A Likert scale was used to rate different qualities (1: not important, 9: very important), and summary statistics are reported as overall means and standard deviations. Analysis of variance comparisons were made between the different Ophthalmic Plastic and Reconstructive Surgery fellow graduate years, gender, and future practice goals. RESULTS: In total, 87 surveys were e-mailed with 67 responses, a 77% response rate. The qualities with the highest mean were variety of surgical procedures (mean ± standard deviation: 8.6 ± 0.7), volume of procedures/surgeries (8.6 ± 0.7), personality of the program director (8.2 ± 1.3), and interview (7.7 ± 1.4). The characteristics that ranked the lowest in descending order were presence of a county hospital (5.1 ± 2.2), proximity to family (4.8 ± 2.7), didactics (4.7 ± 1.9), and benefits (4.4 ± 2.0). There was no statistically significant difference when comparing the groups according to gender and year of graduation. Fellows who want to pursue a career in academic medicine ranked academic fellowships higher in importance (8.0 ± 1.0) than those who wanted a career in private practice (5.3 ± 2.2). CONCLUSIONS: American Society of Ophthalmic Plastic and Reconstructive Surgery fellows place an emphasis on surgical experience, the program director's personality, and the interview process when ranking fellowship training programs. This information is valuable for program directors to better recruit fellows.

Urothelial carcinoma with orbital metastasis.

A case of urothelial carcinoma of the bladder with orbital metastasis in a 53-year-old woman is presented. This case is unique in that the orbit was the sole site of metastasis and extensive lymph node dissection was negative just weeks before the diagnosis of orbital disease. Although rare, patients with urothelial carcinoma and ophthalmic signs or symptoms warrant specialist consultation and appropriate imaging.

Novel formulation of glycerin 1% artificial tears extends tear film break-up time compared with Systane lubricant eye drops.

PURPOSE: To evaluate the effectiveness of glycerin 1% formulated with the novel and proprietary ophthalmic excipient poly(l-lysine)-graft-poly(ethylene glycol) (PLL-g-PEG) (Eyeon Particle Sciences LLC) in extending tear film break-up time (TFBUT) compared with a market-leading artificial tear formulation of propylene glycol (0.3%) and polyethylene glycol (0.4%) (Systane(®) Lubricant Eye Drops; Alcon, Fort Worth, TX). METHODS: This prospective single-center, single visit, randomized, double-masked exploratory trial compared the new formulation and Systane using TFBUT. Noninvasive break-up time (NIBUT) was measured in subjects with asymptomatic to mild (n=5), mild to moderate (n=5), and moderate to severe (n=6) dry eye disease using the TearscopePlus™ at pre-instillation and again at 15, 30, 60, and 120 min after instillation. Fluorescein break-up time (FBUT) was measured at 120 min after instillation. RESULTS: At 15 min (N=16), the new formulation extended mean NIBUT by 14.67 s (P=0.05) compared with 7.40 s (P=0.34) by Systane. The new formulation had a mean FBUT of 4.92 s longer than Systane at 120 min (P=0.12). With outliers removed (N=13), the difference between the mean NIBUT change from baseline for the new formulation and Systane at 120 min was statistically significant (P=0.03). CONCLUSIONS: This study demonstrates that PLL-g-PEG as a polymer excipient in artificial tears is effective in improving the performance of demulcents to significantly prolong NIBUT at 15 min, and that protective activity from this artificial tear product for 2 or more hours after eye drop instillation is possible.

Medical management of thyroid eye disease.

Thyroid eye disease (TED) is the most common cause of orbital disease in adults. The immunologic pathogenesis of TED has been an area of active research and considerable progress has resulted in an expansion of therapeutic options. Although surgical intervention may be required, a majority of TED patients can be managed with medical therapies. Of medical therapies, glucocorticoids remain the agent of choice in the control of TED activity. The objective of this review is to discuss the paradigm and options in medical management of TED.

Understanding pediatric bacterial preseptal and orbital cellulitis.

Pediatric preseptal and orbital cellulitis are infectious disorders that result in periorbital inflammation. Preseptal cellulitis is often associated with breaches in the skin barrier whereas orbital cellulitis is commonly associated with paranasal sinusitis. Orbital cellulitis may be associated with subperiosteal abscess. It is important to distinguish between preseptal from orbital cellulitis. Clinical examination and diagnostic imaging are useful in determining appropriate management. Patients are usually treated with broad spectrum antibiotics and surgery when indicated.

Indirect orbital floor fractures: a meta-analysis.

Orbit fractures are common in the context of orbital trauma. Fractures of the orbital floor without orbital rim involvement are known as indirect orbital floor fractures, pure internal floor fractures, and orbital blowout fractures. In this paper, we have reported a meta-analysis of orbital floor fractures focusing on indications and timing of surgical repair, outcomes, and complications.