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.

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.

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.

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.