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Magnetic resonance imaging (MRI) is increasingly used by the orbital surgeon to aid in the diagnosis, surgical planning, and monitoring of orbital disease. MRI provides superior soft tissue detail compared with computed tomography or ultrasound, and advancing techniques enhance its ability to highlight abnormal orbital pathology. Diffusion-weighted imaging is a specialized technique that uses water molecule diffusion patterns in tissue to generate contrast signals and can help distinguish malignant from benign lesions. Steady-state free precession sequences such as Constructive Interference in Steady-State (CISS) and Fast Imaging Employing Steady-state Acquisition (FIESTA) generate highly detailed, 3-dimensional reconstructed images and are particularly useful in distinguishing structures adjacent to cerebral spinal fluid. Magnetic resonance angiography can be used to characterize vascular lesions within the orbit. New developments in magnetic field strength as well as the use of orbital surface coils achieve increasingly improved imaging resolution.

A young, morbidly obese woman with recent SARS-CoV-2 infection requiring hospitalization presented with visual and neurologic complications secondary to bilateral cerebral venous sinus thromboses. With elevated intracranial pressure and severe papilledema, she rapidly progressed to complete bilateral vision loss despite anticoagulation, therapeutic lumbar punctures with lumbar drain, bilateral optic nerve sheath fenestrations, and endovascular thrombectomy. It is possible that obese patients with a SARS-CoV-2 infection may be at greater risk of hypercoagulable cerebrovascular complications. It is impossible to know if an even more rapid response would have led to a different outcome, but we report this case in the hope that publishing this and similar cases may result in improved treatment protocols to preserve vision.

In response to the coronavirus (COVID-19) pandemic, teprotumumab production was temporarily halted with resources diverted toward vaccine production. Many patients who initiated treatment with teprotumumab for thyroid eye disease were forced to deviate from the standard protocol. This study investigates the response of teprotumumab when patients receive fewer than the standard 8-dose regimen.This observational cross-sectional cohort study included patients from 15 institutions with active or minimal to no clinical activity thyroid eye disease treated with the standard teprotumumab infusion protocol. Patients were included if they had completed at least 1 teprotumumab infusion and had not yet completed all 8 planned infusions. Data were collected before teprotumumab initiation, within 3 weeks of last dose before interruption, and at the visit before teprotumumab reinitiation. The primary outcome measure was reduction in proptosis more than 2 mm. Secondary outcome measures included change in clinical activity score (CAS), extraocular motility restriction, margin reflex distance-1 (MRD1), and reported adverse events.The study included 74 patients. Mean age was 57.8 years, and 77% were female. There were 62 active and 12 minimal to no clinical activity patients. Patients completed an average of 4.2 teprotumumab infusions before interruption. A significant mean reduction in proptosis (-2.9 mm in active and -2.8 mm in minimal to no clinical activity patients, P0.01) was noted and maintained during interruption. For active patients, a 3.4-point reduction in CAS (P0.01) and reduction in ocular motility restriction (P0.01) were maintained during interruption.Patients partially treated with teprotumumab achieve significant reduction in proptosis, CAS, and extraocular muscle restriction and maintain these improvements through the period of interruption.

The orbit houses and protects the ocular globe and the supporting structures, and occupies a strategic position below the anterior skull base and adjacent to the paranasal sinuses. Its embryologic origins are inextricably intertwined with those of the central nervous system, skull base, and face. Although the orbit contains important contributions from four germ cell layers (surface ectoderm, neuroectoderm, neural crest, and mesoderm), a significant majority originate from the neural crest cells. The bones of the orbit, face, and anterior cranial vault are mostly neural crest in origin. The majority of the bones of the skull base are formed through endochondral ossification, whereas the cranial vault is formed through intramembranous ossification. Familiarity with the embryology and fetal development of the orbit can aid in understanding its anatomy, as well as many developmental anomalies and pathologic conditions that affect the orbit.

PURPOSE To determine the efficacy of a frontalis muscle flap eyelid reanimation technique for correction of severe congenital ptosis and associated amblyopia in infants. METHODS The authors performed a retrospective chart review of patients 12 months of age or younger with unilateral or bilateral congenital ptosis and associated amblyopia or deemed at high risk for amblyopia due to visual deprivation. Following ptosis repair via a frontalis muscle flap technique, primary outcomes of postoperative eyelid position and amblyopia reversal were assessed. RESULTS Seventeen eyes of 12 participants were included for study. Seven of these patients had simple congenital ptosis, and the remainder had ptosis as part of a syndrome. Nine were diagnosed with amblyopia preoperatively, and the remaining 3 were too young for acuity testing but had occlusion of the visual axis by the ptotic eyelid in primary gaze. Postoperatively, the mean margin-to-reflex distance 1 was 2.4 mm (range: 0.0-4.0), and 9 patients (75%) demonstrated no evidence of amblyopia. Only 2 patients had eyelid asymmetry greater than 2 mm, which in both cases was due to lack of frontalis activation by the patient secondary to ongoing visual impairment. The most common complication was lagophthalmos in 6 eyes (35.3%), with no significant associated surface keratopathy. CONCLUSIONS The frontalis muscle flap technique may offer a new and effective approach to treating infants with severe congenital ptosis causing poor eyelid excursion and associated amblyopia while avoiding use of an implant.

Purpose Conjunctival cicatrizing conditions are vision threatening, with poor outcomes despite aggressive systemic therapy. This study tests the utility of serial injections of 5-fluorouracil (5-FU) into the fornices to treat conjunctival scarring in patients with ocular cicatricial pemphigoid or Stevens-Johnson syndrome/toxic epidermal necrolysis. Methods Retrospective cohort study. Fisher exact test and multivariable logistic regression analyses were used to compare clinical outcomes of patients who were administered 5-FU injections versus patients who were not injected. Model fit was examined for multivariable regression. Results One hundred twelve eyes (56 patients) met the inclusion criteria. Thirty-eight eyes (34%) had Stevens-Johnson syndrome/toxic epidermal necrolysis, and 74 eyes (66%) were diagnosed with ocular cicatricial pemphigoid. Twenty-five eyes received ≥1 injection of 5-FU. Sixteen eyes received 1-4 injections, while 9 received ≥5. Median follow-up until last encounter was 18 months. Analysis of each disease entity alone and in combination revealed that 5-FU injections were associated with improvement in final visual acuity, corneal scarring, trichiasis, need for/number of mucous membrane graft surgeries, and severity of symblephara. Conclusions Serial injection of 5-FU in the affected fornices is a promising treatment for severe vision-threatening conjunctival scarring from ocular cicatricial pemphigoid and Stevens-Johnson syndrome/toxic epidermal necrolysis. Given the excellent safety profile of 5-FU around the eye, the solid biologic foundation for using 5-FU in this setting, and the severe risk of vision loss from these disorders, the authors suggest that serial 5-FU injections be adopted as therapy for conjunctival scarring from ocular cicatricial pemphigoid or Stevens-Johnson syndrome/toxic epidermal necrolysis despite the limitations of this retrospective study.

Rationale and Objectives Surgical repair of an isolated orbital fracture requires anatomically accurate implant shape and placement. We describe a three-dimensional (3D) printing technique to customize the shape of commercially available absorbable implants. Materials and Methods We reviewed our early experience with three cases in which 3D printed molds were utilized for fracture repair. The institution's medical records were reviewed to assess operative time for orbital floor blow-out fracture repairs. Thin section computed tomography (CT) images were loaded into a clinical 3D visualization software, and stereolithography models were created. The models were loaded into stereolithography editing software in which the nonfractured side was mirrored and overlaid with the fractured side. Sterilizable 3D printed molds were created using the fracture images as well as the virtual mirrored images. The molds were taken to the operating room and used to shape a customized orbital implant for fracture repair, using off-the-shelf bioabsorbable implants. Results The three patients treated using 3D printed molds had excellent outcomes, with decreased postoperative edema and rapid resolution of ocular misalignment/strabismus. Surgical times were decreased from an average of 93.3 minutes using standard implants to 48.3 minutes following adoption of 3D printed molds. Conclusion Three-dimensional printed models can be used to create molds for shaping bioabsorbable implants for customized surgical repair, improving fit, reducing tissue handling and postoperative edema, and reducing surgical times.

Purpose To perform a comprehensive review of dermis fat graft (DFG) in socket reconstruction and illustrate the technical nuances and outcomes using a retrospective case review. Methods A literature search of 143 texts was reviewed. A retrospective case series of 34 patients following primary or secondary DFG after enucleation at a single institution (2009-2019) was performed. Clinical outcomes were statistically analyzed. Variables investigated included age, sex, race, surgical indication, muscle reattachment, complications, motility, eyelid position, prosthesis fit, and need for additional surgery. Results The history of DFG, use in socket reconstruction, primary and secondary indications, and surgical techniques are described. Thirty-two adults and 2 pediatric cases of DFG were reviewed; 18.75% indications were primary and 81.25% were secondary. Good eyelid position was observed in 83.3% of patients with primary DFG versus 37.5% with secondary DFG (p = 0.07). Postoperative complications occurred in 58.8% of patients, were typically mild, and resolved with minimal or no intervention. No statistically significant differences were found between occurrence of any particular complication in primary versus secondary DFG placement (p = 0.36) or between primary and secondary DFG placement and the need for additional surgery (p = 1.0). Among the 67.7% patients who had implant exposure or extrusion as an indication for DFG, 39.1% required additional surgery within 2 years. Advanced age was not associated with higher complication rates (p = 0.12). Conclusions DFG is an excellent option for socket reconstruction, particularly in cases involving pediatric patients, complicated orbits, history of multiple previous surgeries, and inflamed, contracted, or scarred sockets.

Tumor mesenchymal transformation (MT) is a hallmark of high-grade gliomas. The mesenchymal state is associated with specific changes related to cell adhesion, migration, and the extracellular matrix. Collagen 1a1 (COL1A1) is a main component of the extracellular matrix in gliomas, and its expression correlates inversely with patient survival. However, the cellular and molecular mechanisms of the tumor-associated COL1A1 matrix in gliomas remains elusive. Our study integrates histopathological features, spatially resolved transcriptomics, cellular dynamics and microenvironment alterations associated with MT in high-grade gliomas. Using deep learning analysis of mouse and human glioma histological samples we identified that the density of areas of MT, named oncostreams, correlates with tumor aggressiveness. Spatial transcriptomics analysis, using laser capture microdissection, identified a signature enriched in extracellular matrix related proteins, in which COL1A1 appeared as a key determinant of mesenchymal organization. Correspondingly, human and mouse high-grade gliomas showed prominent alignment of collagen fibers along these mesenchymal fascicles and higher COL1A1 expression compared to low-grade gliomas. Moreover, RNA fluorescent multiplex assays identified at single cell level that different cells within glioma tumors contribute to COL1A1 expression, including neoplastic cells and perivascular non-neoplastic cells such as ACTA2+, CYR61+ and FAP+. Inhibition of COL1A1 using genetically engineered mouse models decreased areas of mesenchymal transformation and increased survival. COL1A1 downregulation impaired tumor cell proliferation and remodeled the tumor microenvironment by reducing CD68+ macrophages/microglia cells, CD31+ endothelial cells, ACTA2+, CYR61+ and FAP+ perivascular cells, and increased GFAP+ astrocytes infiltration withing the tumor mass. Further studies, using ex-vivo glioma explants demonstrated that CO1A1 downregulation decreased collective invasion of the normal brain, supporting its importance in tumor progression. We propose that COL1A1 expression is a valuable marker for diagnosis, and COL1A1 depletion within glioma tumors is a promising direct or complementary therapeutic approach to reprogram mesenchymal transformation, and halt tumor growth.

We describe a case of an 18-year-old male who developed a supraorbital neuroma following facial trauma that occurred 2 years earlier. He presented with complaints of persistent facial pain and migraines despite successful laceration repair and removal of foreign bodies at the time of injury. A non-contrast computed tomography (CT) scan of the orbits revealed an enlarged supraorbital nerve with remodeling and expansion of the supraorbital notch, suggesting a neuroma. The patient underwent orbitotomy with excision of neuroma (confirmed histologically) and experienced a complete resolution of periorbital pain.

Purpose Genomic reprogramming and cellular dedifferentiation are critical to the success of de novo tissue regeneration in lower vertebrates such as zebrafish and axolotl. In tissue regeneration following injury or disease, differentiated cells must retain lineage while assuming a progenitor-like identity in order to repopulate the damaged tissue. Understanding the epigenetic regulation of programmed cellular dedifferentiation provides unique insights into the biology of stem cells and cancer and may lead to novel approaches for treating human degenerative conditions. Methods Using a zebrafish in vivo model of adult muscle regeneration, we utilized chromatin immunoprecipitation followed by massively parallel DNA sequencing (ChIP-seq) to characterize early changes in epigenetic signals, focusing on three well-studied histone modifications-histone H3 trimethylated at lysine 4 (H3K4me3), and histone H3 trimethylated or acetylated at lysine 27 (H3K27me3 and H3K27Ac, respectively). Results We discovered that zebrafish myocytes undergo a global, rapid, and transient program to drive genomic remodeling. The timing of these epigenetic changes suggests that genomic reprogramming itself represents a distinct sequence of events, with predetermined checkpoints, to generate cells capable of de novo regeneration. Importantly, we uncovered subsets of genes that maintain epigenetic marks paradoxical to changes in expression, underscoring the complexity of epigenetic reprogramming. Conclusions Within our model, histone modifications previously associated with gene expression act for the most part as expected, with exceptions suggesting that zebrafish chromatin maintains an easily editable state with a number of genes paradoxically marked for transcriptional activity despite downregulation.

To date, there are no studies on healthcare resource utilization (HRU) and costs for treating periocular basal cell carcinoma (pBCC). We investigated real-world HRU and costs of patients with limited versus extensive pBCC.This was a retrospective cost analysis.Administrative claims database was mined for basal cell carcinoma (BCC)-related claims from January 2011 to December 2018. Patients had ≥1 inpatient or ≥2 outpatient nondiagnostic claims for pBCC ≥30 days apart, ≥6 months of continuous enrollment in a health plan before the index date, and ≥18 months of continuous enrollment after the index date. Patients were categorized by disease severity (limited or extensive) using Current Procedural Terminology codes. A total of 1368 patients were propensity matched 1:1 for limited and extensive pBCC (n = 684 each). Outcomes were cost and HRU measures during the 18-month follow-up period.Patients with extensive disease had a higher number of outpatient visits (32.47 vs 28.81; P.0001), radiation therapies (0.53 vs 0.17; P = .001), surgeries (1.82 vs 1.24; P.001), days between first and last surgery (40.82 vs 16.51 days; P.001), outpatient pBCC claims (3.89 vs 3.38; P.001), and days between pBCC claims (170.43 vs 144.01 days; P.001). Patients with extensive disease incurred higher total all-cause costs ($36,986.10 vs $31,893.13; P = .02), outpatient costs ($20,450.26 vs $16,885.87; P = .005), radiation therapy costs ($314.28 vs $89.81; P = .01), and surgery costs ($3,697.08 vs $2,585.80; P.001) than patients with limited disease.Patients with extensive pBCC incurred higher costs, greater HRU, and longer time between first and last surgery versus patients with limited pBCC. Early diagnosis and early treatment of pBCC have economic benefits.

Background Basal cell carcinoma (BCC) is a common skin cancer often curable by excision; however, for patients with BCC around the eye, excision places visual organs and function at risk. In this article, we test the hypothesis that use of the hedgehog inhibitor vismodegib will improve vision‐related outcomes in patients with orbital and extensive periocular BCC (opBCC). Materials and Methods In this open‐label, nonrandomized phase IV trial, we enrolled patients with globe‐ and lacrimal drainage system–threatening opBCC. To assess visual function in the context of invasive periorbital and lacrimal disease, we used a novel Visual Assessment Weighted Score (VAWS) in addition to standard ophthalmic exams. Primary endpoint was VAWS with a score of 21/50 (or greater) considered successful, signifying globe preservation. Tumor response was evaluated using RECIST v1.1. Surgical specimens were examined histologically by dermatopathologists. Results In 34 patients with opBCC, mean VAWS was 44/50 at baseline, 46/50 at 3 months, and 47/50 at 12 months or postsurgery. In total, 100% of patients maintained successful VAWS outcome at study endpoint. Compared with baseline, 3% (95% confidence interval [CI], 0.1–15.3) experienced major score decline (5+ points), 14.7% (95% CI, 5 to 31.1) experienced a minor decline (2–4 points), and 79.4% experienced a stable or improved score (95% CI, 62.1–91.3). A total of 56% (19) of patients demonstrated complete tumor regression by physical examination, and 47% (16) had complete regression by MRI/CT. A total of 79.4% (27) of patients underwent surgery, of which 67% (18) had no histologic evidence of disease, 22% (6) had residual disease with clear margins, and 11% (3) had residual disease extending to margins. Conclusion Vismodegib treatment, primary or neoadjuvant, preserves globe and visual function in patients with opBCC. Clinical trail identification number.NCT02436408. Implications for Practice Use of the antihedgehog inhibitor vismodegib resulted in preservation of end‐organ function, specifically with regard to preservation of the eye and lacrimal apparatus when treating extensive periocular basal cell carcinoma. Vismodegib as a neoadjuvant also maximized clinical benefit while minimizing toxic side effects. This is the first prospective clinical trial to demonstrate efficacy of neoadjuvant antihedgehog therapy for locally advanced periocular basal cell carcinoma, and the first such trial to demonstrate end‐organ preservation., This article reports the results of a prospective clinical trial of vismodegib for patients with basal cell carcinoma occurring in the orbital and periocular regions to assess whether such treatment helps to preserve visual organs and function.

Purpose of review This review aims to bring together recent advances in basic, translational and clinical research on the pathogenesis and treatment of orbital inflammatory conditions. Recent findings Basic science studies provide mechanistic insights into why the orbit is targeted for inflammation by autoimmune inflammatory disorders. Using Graves' disease as a test case reveals that endocrine pathways, such as the TSH and IGF1 receptor pathways play important roles in stimulating orbital inflammation. Furthermore, orbital tissues contain high concentrations of retinoids - byproducts of the visual pathway that diffuse across the sclera and can activate de novo transcription of inflammatory cytokines. Such cytokine expression places the orbit in a hyper-inflammatory 'resting' state, prone to respond to any additional systemic or local pro-inflammatory signals. The HIF2A--LOX pathway appears important for orbital tissue fibrosis. Lastly, bench-to-bedside studies of the IGF1R pathway have led to an FDA-approved drug, teprotumumab that represents a novel treatment approach for Graves' orbitopathy. Unfortunately, high drug costs and misplaced insurance company 'step-therapy' policies may block patients from receiving therapy that can protect vision and improve quality of life. Summary Improved understanding of orbital inflammatory conditions has led to a new drug and promises additional breakthroughs. Translational research is successful, but requires time, resources, and patience.

Glioblastomas multiforme (GBMs) are the most lethal tumors of the brain. Tumoral mesenchymal transformation is a hallmark of GBMs associated with alterations in cellular morphology and dynamic organization. However, little is known about the mechanisms that control this pathological process. Here, we report a comprehensive spatiotemporal study integrating novel intra-tumoral histopathological structures, ‘oncostreams’, with tumor dynamic properties, microenvironment assets and spatial molecular features. Cellular analyses of genetic engineered mouse models of glioma identified that oncostreams are heterogenous structures formed by elongated and aligned neoplastic cells enriched in non-neoplastic cells such as ACTA2+ mesenchymal like cells and CD68+ tumor associated microglia/macrophages (TAM). Deep learning analysis of H&E glioma histological samples from mouse and human gliomas identified that oncostream density correlates with tumor aggressiveness. To determine whether oncostreams fascicles are characterized by a specific gene expression profile, we performed transcriptomic analysis using laser capture microdissection coupled to RNA-sequencing. We found that oncostreams are defined by a transcriptomic signature enriched in mesenchymal genes. Network analyses identified that COL1A1 is a critical gene that regulates oncostream organization and function. Correspondingly, human and mouse high-grade gliomas with high oncostream densities showed prominent alignment of collagen fibers along these fascicles and higher COL1A1 expression compared to low-grade gliomas. To evaluate the functional role of COL1A1 in oncostream formation we generated a COL1A1-deficient GEMM of glioma. We observed that COL1A1 inhibition decreased oncostream formation, impaired tumor cell proliferation and remodeled the tumor microenvironment by diminishing CD68+ TAM cells, CD31+ endothelial vascular proliferation and ACTA2+ perivascular mesenchymal cells, thus increasing animal survival. Further studies, using time lapse confocal imaging in ex vivo glioma explants, and intravital imaging in vivo demonstrated that oncostreams are organized collective dynamic structures present at the tumor core and the invasive tumor border. Oncostreams dynamics increased the intra-tumoral spread of cells within the tumor and foster glioma aggressiveness through collective invasion of the normal brain parenchyma. The analysis of glioma invasion in COL1A1 knockdown tumors exhibited a reduction in collective migration patterns, strongly supporting its importance in tumor progression. We propose that oncostreams represent a novel pathological marker of potential value for diagnosis and COL1A1 depletion within oncostreams is a promising approach and reprogram mesenchymal transformation to reduce the tumor malignancy. Citation Format: Andrea Comba, Syed Faisal, Patrick J. Dunn, Anna E. Argento, Todd C. Hollon, Wajd N. Al-Holou, Maria L. Varela, Daniel B. Zamler, Gunnar L. Quass, Pierre F. Apostolides, Christine E. Brown, Phillip E. E. Kish, Alon Kahana, Celina G. Kleer, Sebastien Motsch, Maria G. Castro, Pedro R. Lowenstein. Spatiotemporal analyses of preclinical glioma models reveal ‘oncostreams’ as dynamic fascicles regulating tumor mesenchymal transformation, invasion, and malignancy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2476.

Intra-tumoral heterogeneity and diffuse infiltration are hallmarks of glioblastoma that challenge treatment efficacy. However, the mechanisms that set up both tumor heterogeneity and invasion remain poorly understood. Herein, we present a comprehensive spatiotemporal study that aligns distinctive intra-tumoral histopathological structures, oncostreams, with dynamic properties and a unique, actionable, spatial transcriptomic signature. Oncostreams are dynamic multicellular fascicles of spindle-like and aligned cells with mesenchymal properties, detected using ex vivo explants and in vivo intravital imaging. Their density correlates with tumor aggressiveness in genetically engineered mouse glioma models, and high-grade human gliomas. Oncostreams facilitate the intra-tumoral distribution of tumoral and non-tumoral cells, and the invasion of the normal brain. These fascicles are defined by a specific molecular signature that regulates their organization and function. Oncostreams structure and function depend on overexpression of COL1A1. COL1A1 is a central gene in the dynamic organization of glioma mesenchymal transformation, and a powerful regulator of glioma malignant behavior. Inhibition of COL1A1 eliminated oncostreams, reprogramed the malignant histopathological phenotype, reduced expression of the mesenchymal associated genes, induced changes in the tumor microenvironment and prolonged animal survival. Oncostreams represent a novel pathological marker of potential value for diagnosis, prognosis, and treatment.

PURPOSE To test whether intraoperative stereotactic navigation during orbital decompression surgery resulted in quantifiable surgical benefit. METHODS This retrospective cohort study examined all consecutive patients who underwent primary orbital decompression surgery for thyroid associated orbitopathy performed by a single surgeon (A.K.) during the periods of 2012-2014 (non-navigated), and 2017-2018 (navigated). The study was HIPAA-compliant, was approved by the Institutional Review Board, and adhered to the tenets of the Helsinki declaration. Recorded parameters included patient age, sex, race, decompression technique (side of operation and walls decompressed), estimated blood loss (EBL), intraoperative complications, times that patient entered and exited the operating room (OR), times of surgical incision and dressing completion, pre- and postoperative best corrected visual acuity (BCVA), proptosis, diplopia, postoperative change in strabismus deviation, and need for subsequent strabismus surgery. Recorded times were used to calculate operating time (initial incision to dressing) and maintenance time (time between OR entry and initial incision and time between dressings and OR exit). The total maintenance time was averaged over total number of operations. Student t test was used to compare surgical times, maintenance times, EBL, and proptosis reduction. Fisher exact test was used to compare BCVA change, strabismus deviation change, resolution or onset of diplopia, and need for corrective strabismus surgery. RESULTS Twenty-two patients underwent primary orbital decompression surgery without navigation, and 23 patients underwent navigation-guided primary orbital decompression surgery. There were no intraoperative complications in either group. The average operative time was shorter in the navigated group for a unilateral balanced decompression (n = 10 vs. 19; 125.8 ± 13.6 vs. 141.3 ± 19.4 min; p-value = 0.019), and a unilateral lateral wall only decompression (n = 13 vs. 3; 80.5 ± 12.8 vs. 93.0 ± 6.1 min; p-value = 0.041). The average maintenance time per surgery was not significantly different between the non-navigated group (51.3 ± 12.7 min) and the navigated group (50.5 ± 6.4 min). There was no significant difference between the navigated and non-navigated groups in average EBL per surgery. There was no significant difference in BCVA change. Average proptosis reduction was larger in the navigated group, but this was not significant. There was a significantly lower proportion of patients who required corrective strabismus surgery following decompression in the navigated group than in the non-navigated group (39.1% vs. 77.3%, p-value = 0.012). CONCLUSIONS Intraoperative stereotactic navigation during orbital decompression surgery has the potential to provide the surgeon with superior spatial awareness to improve patient outcomes. This study found that use of intraoperative navigation reduced operative time (even without factoring in a resident teaching component) while also reducing the need for subsequent strabismus surgery. This study is limited by its size but illustrates that use of intraoperative navigation guidance has substantive benefits in orbital decompression surgery.

The transcranial approach to the orbit requires specialized knowledge, skill, and instrumentation. It can be performed by neurosurgeons but is commonly approached collaboratively, with an orbital, skull base, and/or craniofacial plastic surgeon joining the neurosurgical team to provide specialized skills. The role of the ophthalmic plastic surgeon, as an orbital specialist, includes preoperative evaluation and planning, intraoperative anatomic expertise, and postoperative care.

Surgical management of thyroid eye disease (TED) has two general aims: (1) relieve symptoms of orbital congestion and fibrosis, including possibly compressive optic neuropathy, and (2) reconstruct the periocular region to reduce deformity and renormalize appearance. Surgical management follows a sequence that is tailored to individual patient needs. The signs and symptoms of TED that can be addressed surgically include proptosis, orbital pressure/pain, orbital inflammatory signs, diplopia secondary to restrictive strabismus, ocular surface exposure secondary to lagophthalmos, and eyelid retraction. Because orbital decompression surgery can improve lagophthalmos and eyelid retraction, and can affect strabismus (positively or negatively), these issues are traditionally addressed sequentially by orbital decompression first, followed by strabismus surgery, and finally eyelid retraction repair, as needed. In this chapter, we focus primarily on orbital decompression surgery and eyelid surgery, although key aspects of strabismus surgery are also discussed.

Thyroid eye disease (TED) is caused by an inflammatory process involving the orbit and periorbital tissues in the setting of autoimmune thyroiditis. TED has been shown not only to impact visual and social functioning but also to reduce patients’ quality of life. Thyroid dysfunction in TED most frequently involves hyperthyroidism secondary to Graves’ disease (GD); hypothyroidism secondary to Hashimoto’s thyroiditis, or subclinical inflammation, are involved less commonly. Approximately 25–50% of patients with GD will develop clinically apparent TED some time during their lifetime. Sight-threatening disease is infrequent and occurs in approximately 3–5% of patients. In contrast, subclinical manifestations, including radiographic evidence of enlargement of extraocular muscles, may be present in a larger subset of patients.

Stereotaxy involves the use of computerized technology to identify a point in three dimensions using a Cartesian coordinate system, which can be used for preoperative surgical planning and intraoperative computer-assisted surgical navigation. Stereotactic technology allows for the visualization of surgical anatomy and instrument placement intraoperatively in real-time on preoperatively acquired images, typically computed tomography (CT), magnetic resonance imaging (MRI), or CT-MRI fusion studies. Image-guided surgery has modernized a variety of surgical interventions, including radiosurgery, biopsy, implantation, resection, stimulation, and reconstruction. Although neurosurgery is the field that most frequently utilizes stereotaxy, skull base surgery, otolaryngology, oral and maxillofacial surgery (OMFS), orthopedic surgery, and other medical specialties have also appropriated image-guided surgery into their armamentarium, with notable improvements in patient outcomes. Importantly, the use of stereotactic navigation has been extended to orbital surgery by neurosurgeons, skull base surgeons, and OMF surgeons – a natural extension of this useful surgical tool.

Periocular skin is highly prone to malignancies, especially basal cell and squamous cell carcinomas. Because of the complex anatomy and eye-protecting functions of the periocular tissues, treatment of these cancers requires special considerations. Mohs micrographic surgery is usually the treatment of choice, whenever possible, in order to enhance margin control while limiting collateral damage to nearby normal structures. Cancer excision, whether by Mohs or other techniques, will leave a complex defect that requires careful anatomical and functional reconstruction. This study presents some of the challenges of treating periocular skin cancer and associated reconstructive surgery and provides an intellectual framework for addressing these challenges. The key topics are adherence to anatomical landmarks and aesthetic units, proper distribution of tension, and matching the correct reconstructive approach, that is, type of flap or graft, to the defect at hand. This review is not meant to be exhaustive, but it will provide both basic and advanced considerations.

Zebrafish have the ability to regenerate damaged cells and tissues by activating quiescent stem and progenitor cells or reprogramming differentiated cells into regeneration-competent precursors. Proliferation among the cells that will functionally restore injured tissues is a fundamental biological process underlying regeneration. Midkine-a is a cytokine growth factor, whose expression is strongly induced by injury in a variety of tissues across a range of vertebrate classes. Using a zebrafish Midkine-a loss of function mutant, we evaluated regeneration of caudal fin, extraocular muscle and retinal neurons to investigate the function of Midkine-a during epimorphic regeneration. In wildtype zebrafish, injury among these tissues induces robust proliferation and rapid regeneration. In Midkine-a mutants, the initial proliferation in each of these tissues is significantly diminished or absent. Regeneration of the caudal fin and extraocular muscle is delayed; regeneration of the retina is nearly completely absent. These data demonstrate that Midkine-a is universally required in the signaling pathways that convert tissue injury into the initial burst of cell proliferation. Further, these data highlight differences in the molecular mechanisms that regulate epimorphic regeneration in zebrafish.

Gliomas are primary brain tumors characterized by their invasiveness and heterogeneity. Specific histological patterns such as pseudopalisades, microvascular proliferation, mesenchymal transformation and necrosis characterize the histological heterogeneity of high-grade gliomas. Our laboratory has demonstrated that the presence of high densities of mesenchymal cells, named oncostreams, correlate with tumor malignancy. We have developed a unique approach to understand the mechanisms that underlie glioma’s growth and invasion. Here, we describe a comprehensive protocol that utilizes laser capture microdissection (LMD) and RNA sequencing to analyze differential mRNA expression of intra-tumoral heterogeneous multicellular structures (i.e., mesenchymal areas or areas of tumor invasion). This method maintains good tissue histology and RNA integrity. Perfusion, freezing, embedding, sectioning, and staining were optimized to preserve morphology and obtain high-quality laser microdissection samples. The results indicate that perfusion of glioma bearing mice using 30% sucrose provides good morphology and RNA quality. In addition, staining tumor sections with 4% Cresyl violet and 0.5% eosin results in good nuclear and cellular staining, while preserving RNA integrity. The method described is sensitive and highly reproducible and it can be utilized to study tumor morphology in various tumor models. In summary, we describe a complete method to perform LMD that preserves morphology and RNA quality for sequencing to study the molecular features of heterogeneous multicellular structures within solid tumors.