Multispecialty Management of Metastatic Colon Adenocarcinoma Involving the Extraocular Muscles: Primary Excision and Simultaneous Treatment of Strabismus With a Review of the Literature.

Metastatic colon adenocarcinoma involving the extraocular muscles is extremely rare. It usually develops following the diagnosis of the systemic disease and therefore, management and treatment require a multispecialty approach. Within this manuscript, we provide a summary of cases of orbital metastasis secondary to colon cancer. We further discuss a detailed case of a 42-year-old male patient who developed recent-onset diplopia in the left gaze. Orbital CT imaging showed a localized, well-circumscribed enlargement of the right medial rectus muscle. The biopsy of the right medial rectus showed adenocarcinoma originating from the gastrointestinal system. Further workup revealed colon adenocarcinoma with multiple metastatic sites. The patient started systemic chemotherapy. After 2 months of chemotherapy (5-fluouracil, oxaliplatin, irinotecan, and leucovorin), all systemic metastatic sites regressed; however, his medial rectus muscle continued to grow, causing compressive optic neuropathy. The patient underwent excisional biopsy of the right medial rectus muscle with simultaneous repair of the strabismus with transposition of superior and inferior recti muscles. He continued with systemic chemotherapy. Follow up in 1 year revealed no local orbital tumor recurrence with excellent visual acuity and no diplopia in primary gaze.

Variants in myelin regulatory factor (MYRF) cause autosomal dominant and syndromic nanophthalmos in humans and retinal degeneration in mice.

Nanophthalmos is a rare, potentially devastating eye condition characterized by small eyes with relatively normal anatomy, a high hyperopic refractive error, and frequent association with angle closure glaucoma and vision loss. The condition constitutes the extreme of hyperopia or farsightedness, a common refractive error that is associated with strabismus and amblyopia in children. NNO1 was the first mapped nanophthalmos locus. We used combined pooled exome sequencing and strong linkage data in the large family used to map this locus to identify a canonical splice site alteration upstream of the last exon of the gene encoding myelin regulatory factor (MYRF c.3376-1G>A), a membrane bound transcription factor that undergoes autoproteolytic cleavage for nuclear localization. This variant produced a stable RNA transcript, leading to a frameshift mutation p.Gly1126Valfs*31 in the C-terminus of the protein. In addition, we identified an early truncating MYRF frameshift mutation, c.769dupC (p.S264QfsX74), in a patient with extreme axial hyperopia and syndromic features. Myrf conditional knockout mice (CKO) developed depigmentation of the retinal pigment epithelium (RPE) and retinal degeneration supporting a role of this gene in retinal and RPE development. Furthermore, we demonstrated the reduced expression of Tmem98, another known nanophthalmos gene, in Myrf CKO mice, and the physical interaction of MYRF with TMEM98. Our study establishes MYRF as a nanophthalmos gene and uncovers a new pathway for eye growth and development.

"Tag-Team" Orbital and Strabismus Surgeries with Immediate Reconstruction After Tumor Excision Metastatic to the Inferior Rectus.

Carcinoid tumors are rare, slow-growing, low-grade neuroendocrine tumors with a propensity for orbital metastatic spread. The typical treatment paradigm for localized orbital disease involves excision, adjuvant radiotherapy, and/or receptor-targeted chemotherapy, followed by delayed evaluation for reconstructive strabismus surgery. We present a 58-year-old female patient with carcinoid tumor metastatic to the right inferior rectus muscle who presented with worsening binocular diplopia. The patient underwent coordinated "tag-team" orbital and strabismus surgeries that included excision of the right inferior rectus muscle to the annulus of Zinn followed immediately by reconstructive strabismus surgery. The patient required 1 additional strabismus surgery 1 year later. Follow up revealed no tumor recurrence at 4 years, and excellent binocular vision with good function. Deep orbital and strabismus surgeries, when performed simultaneously in a "tag-team" approach, may offer superior functional outcomes and improved patient quality of life, with expedited functional recovery. This approach may become a new treatment paradigm for surgical disease processes localized to the extraocular muscles.

Characterization and pharmacologic targeting of EZH2, a fetal retinal protein and epigenetic regulator, in human retinoblastoma.

Retinoblastoma (RB) is the most common primary intraocular cancer in children, and the third most common cancer overall in infants. No molecular-targeted therapy for this lethal tumor exists. Since the tumor suppressor RB1, whose genetic inactivation underlies RB, is upstream of the epigenetic regulator EZH2, a pharmacologic target for many solid tumors, we reasoned that EZH2 might regulate human RB tumorigenesis. Histologic and immunohistochemical analyses were performed using an EZH2 antibody in sections from 43 samples of primary, formalin-fixed, paraffin-embedded human RB tissue, cryopreserved mouse retina, and in whole cell lysates from human RB cell lines (Y79 and WERI-Rb1), primary human fetal retinal pigment epithelium (RPE) and fetal and adult retina, mouse retina and embryonic stem (ES) cells. Although enriched during fetal human retinal development, EZH2 protein was not present in the normal postnatal retina. However, EZH2 was detected in all 43 analyzed human RB specimens, indicating that EZH2 is a fetal protein expressed in postnatal human RB. EZH2 expression marked single RB cell invasion into the optic nerve, a site of invasion whose involvement may influence the decision for systemic chemotherapy. To assess the role of EZH2 in RB cell survival, human RB and primary RPE cells were treated with two EZH2 inhibitors (EZH2i), GSK126 and SAH-EZH2 (SAH). EZH2i impaired intracellular adenosine triphosphate (ATP) production, an indicator of cell viability, in a time and dose-dependent manner, but did not affect primary human fetal RPE. Thus, aberrant expression of a histone methyltransferase protein is a feature of human RB. This is the first time this mechanism has been implicated for an eye, adnexal, or orbital tumor. The specificity of EZH2i toward human RB cells, but not RPE, warrants further in vivo testing in animal models of RB, especially those EZH2i currently in clinical trials for solid tumors and lymphoma.

Resolution of cyclic esotropia with 5-year follow-up after brief Fresnel prism treatment.

Cyclic esotropia is a rare form of strabismus that is characterized by a recurring esotropic deviation, usually with a 48-hour cycle. On esotropic days, the patient has a constant deviation with suppression, followed by a day with straight eyes and good binocular function. We report a case of cyclic esotropia in which the cycling resolved with 2 months of Fresnel prism for the amount of the distance deviation on her "straight" days. Five years later, with low plus hyperopic correction, she remains with a stable esophoria and normal stereopsis.

Small tuck for superior oblique palsy.

PURPOSE: To investigate the surgical outcomes of small superior oblique (SO) tuck-denoting minimal tendon laxity-in patients with unilateral SO palsy. METHODS: The medical records of consecutive patients treated with ≤6 mm SO tuck from 2000 to 2018 at Kellogg Eye Center, University of Michigan, were reviewed retrospectively. Tendon tucks were performed to a fairly uniform tension in an amount that just eliminated slack in the tendon. Pre- and postoperative motility measurements were compared. Patients were excluded if they had a history of prior strabismus surgery or concurrent vertical rectus or inferior oblique surgery. RESULTS: A total of 27 cases (14 males) met inclusion criteria. The median age at surgery was 47 years (range 3-74 years). The mean SO tuck (total, both arms of tuck) was 4.9 mm (range, 2-6 mm). After surgery, median hypertropia decreased from 9Δ to 1Δ in primary position and from 20Δ to 4Δ in the SO field of action (contralateral downgaze). Lateral incomitance (difference in hypertropia between contralateral and ipsilateral gaze) decreased from 10Δ to 2Δ (P < 0.001 in each case). Six patients had diplopia in upgaze postoperatively that was not symptomatic enough to require reoperation. Six patients had residual hypertropia requiring additional surgery. CONCLUSIONS: Small SO tuck provided disproportionate correction of hypertropia in the SO field of action and nearly eliminated lateral incomitance without producing unacceptable iatrogenic Brown syndrome. Even in the absence of tendon laxity, SO tuck was a good surgical option for SO palsy in our cohort where there was marked lateral incomitance and the greatest deviation was in the SO field of action.

Recurrent orbital schwannomas: clinical course and histopathologic correlation.

BACKGROUND: Schwannomas are slow-growing typically encapsulated tumors composed of differentiated Schwann cells, the primary class of peripheral glial cells. Complete excision is the treatment of choice for orbital schwannomas that cause pain, disfigurement, diplopia, or optic neuropathy. The presence of multiple schwannomas in a single patient suggests possible association with neurofibromatosis type 2 (NF2) or schwannomatosis. CASE PRESENTATION: We present 2 patients who experienced recurrent orbital schwannoma without evidence for neurofibromatosis. The recurrence in one patient, a 59-year old man, occurred 6 years after complete excision of the initial tumor. This recurrence consisted of 2 independent tumors in the same orbit. The recurrence in the second patient, a 5 year-old girl, occurred multiple times within days to weeks of partial excisions until eventually a complete excision was performed. CONCLUSION: The clinical history, histopathologic features and particularly the intraoperative findings suggest that the 59 year old man suffers from orbital schwannomatosis, while the rapid recurrence in the second patient correlated with the cellular features of her plexiform schwannoma. Hence, the recurrence in each patient is linked to a different etiology, with implications for treatment and patient counseling given the difficulty in treating orbital schwannomatosis. To our knowledge, this is the first description of isolated orbital schwannomatosis.

Comparison of Unilateral and Bilateral Surgical Approaches for the Treatment of Age-Related Divergence Insufficiency Esotropia.

PURPOSE: Age-related divergence insufficiency-esotropia (ARDIE) is characterized by greater esodeviation at distance than near. This study aims to compare the outcomes of unilateral and bilateral surgical approaches. PATIENTS AND METHODS: Sixty-two cases treated at the Kellogg Eye Center, the University of Michigan, from 1995 to 2018 were retrospectively reviewed. One surgeon used unilateral procedures including unilateral medial rectus recession (n = 24, group 1) or unilateral recession-resection (n = 18, group 2) with an adjustable suture. Another surgeon used bilateral medial rectus recession with fixed sutures (n = 20, group 3). RESULTS: For patients with distance esodeviation <15∆, postoperative distance deviations in both group 1 and group 3 were not statistically different (p = .352). For patients with esodeviations 15-20∆, postoperative distance deviations in all 3 groups were also not statistically different (p = .142). Similarly, patients with deviations >20∆ did not show significantly different postoperative distance alignment (p = .082) between group 2 and 3. Overall, group 2 had the highest overall success rate (90%) (mean at distance = 1.17∆ exodeviation, at near = 2.33∆ exodeviation). CONCLUSION: Both unilateral medial rectus recession ± lateral rectus resection and bilateral medial rectus recession surgical approaches produced similar favorable outcomes in ARDIE.

A 2020 Update on 20/20 X 2: Diplopia after Ocular Surgery: Diplopia after Orbital Surgery.

In a review of 261 strabismus surgeries performed after previous orbital surgery, it was found that diplopia associated with orbital surgery most commonly occurs after orbital decompression for thyroid eye disease or after repair of orbital fractures. Other types of orbital surgery account for only a small number of cases. While the orbital surgery itself may contribute to the development or worsening of diplopia, in most cases, the post-operative strabismus is largely attributable to the underlying disease or trauma. However, in a small number of cases, a specific surgical misadventure can result in diplopia.

Novel TMEM98, MFRP, PRSS56 variants in a large United States high hyperopia and nanophthalmos cohort.

Nanophthalmos is a rare condition defined by a small, structurally normal eye with resultant high hyperopia. While six genes have been implicated in this hereditary condition (MFRP, PRSS56, MYRF, TMEM98, CRB1,VMD2/BEST1), the relative contribution of these to nanophthalmos or to less severe high hyperopia (≥ + 5.50 spherical equivalent) has not been fully elucidated. We collected probands and families (n = 56) with high hyperopia or nanophthalmos (≤ 21.0 mm axial length). Of 53 families that passed quality control, plausible genetic diagnoses were identified in 10/53 (18.8%) by high-throughput panel or pooled exome sequencing. These include 1 TMEM98 family (1.9%), 5 MFRP families (9.4%), and 4 PRSS56 families (7.5%), with 4 additional families having single allelic hits in MFRP or PRSS56 (7.5%). A novel deleterious TMEM98 variant (NM_015544.3, c.602G>C, p.(Arg201Pro)) segregated with disease in 4 affected members of a family. Multiple novel missense and frameshift variants in MFRP and PRSS56 were identified. PRSS56 families were more likely to have choroidal folds than other solved families, while MFRP families were more likely to have retinal degeneration. Together, this study defines the prevalence of nanophthalmos gene variants in high hyperopia and nanophthalmos and indicates that a large fraction of cases remain outside of single gene coding sequences.

Age at Craniosynostosis Surgery and Its Impact on Ophthalmologic Diagnoses: A Single-Center Retrospective Review.

BACKGROUND: Ocular abnormalities in craniosynostosis are a persistent concern for patients and providers, and some surgeons feel that early surgical intervention for synostosis alleviates the progression of ophthalmologic abnormalities. In contradistinction, the authors hypothesize that operating early will have no bearing on postoperative ophthalmologic outcomes. METHODS: Single-suture craniosynostosis patients who underwent surgical correction between 1989 and 2015 were reviewed. Patients with multisuture craniosynostosis, syndromic diagnoses, no preoperative ophthalmology evaluation, and less than 2 years of follow-up were excluded. Logistic regression was used to determine odds of preoperative and postoperative ophthalmologic abnormalities by age, while controlling for patient-level covariates. RESULTS: One hundred seventy-two patients met inclusion criteria. The median age at surgery was 10 months (interquartile range, 7 to 12.9 months). Increasing age at the time of surgery was associated with increased odds of preoperative ophthalmologic diagnoses (OR, 1.06; p = 0.037) but not postoperative diagnoses (OR, 1.00; p = 0.91). Increasing age at surgery was also not associated with increased odds of ophthalmologic diagnoses, regardless of timing (OR, 1.04; p = 0.08). Patients with coronal synostosis (OR, 3.94; p = 0.036) had significantly higher odds of preoperative ophthalmologic diagnoses. Patients with metopic (OR, 5.60; p < 0.001) and coronal (OR, 7.13; p < 0.001) synostosis had significantly higher odds of postoperative ophthalmologic diagnoses. CONCLUSIONS: After reviewing an expansive cohort, associations of both overall and postoperative ophthalmologic diagnoses with age at surgery were not found. The authors' findings thus run counter to the theory that early surgical intervention lessens the likelihood of postoperative ophthalmologic diagnoses and improves ophthalmologic outcomes. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.

Surgical Management of Ophthalmoplegia.

Surgical management-depending upon the severity of the ophthalmoplegia-ranges from restorative to palliative. In paresis with reasonable residual muscle function and ductions, the goal of the surgery is not only to restore single vision in primary position but also to provide a relatively normal field of single binocular vision. With complete paralysis of a single muscle or more than one muscle served by a single cranial nerve (third), in addition to conventional recess or resect surgery, the transposition of still-functioning muscles is often needed to obtain a durable result and restore at least some field of single binocular vision. In complete ophthalmoplegia, the benefits of the surgery are limited; but even in these cases, surgery can often reduce the need for an awkward head posture and improve appearance.

Why strabismus surgery works: the legend of the dose-response curve.

BACKGROUND: The dose-response relationship has historically been regarded as an important approach to improve the success of strabismus surgery. The purpose of this study was to explore the role of preoperative deviation, in addition to the amount of surgery, as a predictor of the response to strabismus surgery. METHODS: Dose-response data from a variety of sources are analyzed in a multiple linear regression model with both preoperative deviation and surgical dose as independent variables. P values and partial correlations from these regressions are used to investigate the relative contribution of each factor. RESULTS: These analyses consistently show that preoperative deviation is statistically a better predictor of the response to surgery than the amount of surgery. In data sets where one factor is constant, preoperative deviation alone accounts for 78%, and the amount of surgery alone accounts for 46% of the variance of the surgical response. CONCLUSIONS: The importance of preoperative deviation as an independent variable implies a biologic response to strabismus surgery that tends to produce more change in alignment when the deviation is large and less when it is small. The strong association of amount of surgery with surgical outcome in bivariate analysis studies may be an artifact of making the amount of surgery a strict function of the preoperative deviation. Because of its lesser role as a predictor, accuracy of preoperative deviation measurement upon which the amount of surgery is based, refinement of the dose-response curve, or use of adjustable sutures may have less potential to improve surgical outcome than generally believed.

The effect of oral statin therapy on strabismus in patients with thyroid eye disease.

BACKGROUND: Statins, known to possess anti-inflammatory characteristics, have recently been identified as potentially reducing the risk of developing thyroid eye disease (TED) in Graves disease patients. The current study investigates the effect of oral statin therapy on strabismus related to TED. METHODS: This is a retrospective review of patients with a diagnosis of both TED and restrictive strabismus. Oral statin users and nonusers were analyzed for smoking status, previous radioactive iodine, thyroidectomy, number of decompressions, motility restriction, amount of strabismus, number of surgeries, surgical dose, and number of muscles involved on radiography. RESULTS: Thirty patients (average age, 63.9 years; 50% male; 59% current/former smokers) were included: 12 statin users and 18 nonusers. Statin users averaged fewer decompressions (1.3 in users vs 2.4 in nonusers [P = 0.04]). Statin users on average had 15 mm of total strabismus surgery compared with 21.4 mm in the nonuser group (P = 0.09) and had fewer muscles involved radiographically (4.3 vs 5.1 [P = 0.08]) CONCLUSIONS: Compared to nonusers, statin users tended to have fewer decompressions, less restriction, fewer surgeries, and fewer muscles involved despite having more current smokers (36% vs 5%), more males, more RAI, and fewer thyroidectomies, all of which are associated with worse TED. In our cohort of patients with TED and strabismus, statin therapy significantly reduced the number of orbital decompressions. Oral statin therapy also trended toward reducing the number and amount of strabismus surgeries as well as radiographic indication of muscle involvement, although these did not meet statistical significance.

Discrepancies between intraocular lens implant power prediction formulas in pediatric patients.

PURPOSE: The SRK II, SRK/T, Holladay I, and Hoffer Q intraocular lens power prediction formulas have been claimed to be interchangeable in their predicted postoperative refractive outcome among pediatric patients. In this study, we evaluated this clinical perception. DESIGN: Mathematical analysis. METHODS: Analytical prediction of implant power using keratometry values up to 55 diopters and axial length values as short as 16 mm was performed for 2 different refractive goals using the optimized intraocular lens constants for the SRK II, SRK/T, Holladay I, Hoffer Q, and Haigis formulas. Comparison graphs for the predicted implant power of each formula were constructed and differences between predicted results of the formulas were plotted. MAIN OUTCOME MEASURE: Predicted implant power. RESULTS: Significant differences in intraocular lens power prediction were found among the Hoffer Q, Holladay I, and SRK II formulas in the pediatric range of axial length and keratometry values. The Holladay I and Haigis formulas were found to be similar in their intraocular lens power prediction. The SRK/T was comparable with the Holladay I and Haigis formulas, but still differed in the high keratometry values. CONCLUSIONS: This analysis demonstrates differences in the intraocular lens power prediction among commonly used formulas for axial length and keratometry values in the pediatric range. It is unclear under what circumstances each of these formulas may be preferred in the pediatric population.

Intraocular lens power calculation in children.

With improving surgical technique and equipment, the acceptable age for placing an intraocular lens in infants and children is becoming younger. The tools for predicting intraocular lens power have not necessarily kept up, as current theoretical and regression intraocular lens power prediction formulas are largely based on adult eyes at axial lengths, anterior chamber depth, and keratometric values much different than those seen in infants. In addition, the adult eye has matured and is no longer growing, whereas the eyes of infants and children may continue to note changes in axial length, keratometric values, and possibly optical characteristics. Another source of error in intraocular lens power selection that is more likely to occur in pediatric patients than in adult patients is inaccuracy in measurement of axial length or keratometric power. A review of current tools and considerations for intraocular lens power prediction in infants and children is presented.