Lejla Vajzovic

Maturation of the Human Fovea: Correlation of Spectral-Domain Optical Coherence Tomography Findings With Histology

PURPOSE To correlate human foveal development visualized by spectral-domain optical coherence tomography (SDOCT) with histologic specimens. DESIGN Retrospective, observational case series. METHODS Morphology and layer thickness of retinal SDOCT images from 1 eye each of 22 premature infants, 30 term infants, 16 children, and 1 adult without macular disease were compared to light microscopic histology from comparable ages. RESULTS SDOCT images correlate with major histologic findings at all time points. With both methods, preterm infants demonstrate a shallow foveal pit indenting inner retinal layers (IRL) and short, undeveloped foveal photoreceptors. At term, further IRL displacement forms the pit and peripheral photoreceptors lengthen; the elongation of inner and outer segments (IS and OS, histology) separates the IS band from retinal pigment epithelium. Foveal IS and OS are shorter than peripheral for weeks after birth (both methods). By 13 months, foveal cone cell bodies stack >6 deep, Henle fiber layer (HFL) thickens, and IS/OS length equals peripheral; on SDOCT, foveal outer nuclear layer (which includes HFL) and IS/OS thickens. At 13 to 16 years, the fovea is fully developed with a full complement of SDOCT bands; cone cell bodies >10 deep have thin, elongated, and tightly packed IS/OS. CONCLUSIONS We define anatomic correlates to SDOCT images from normal prenatal and postnatal human fovea. OCT bands typical of photoreceptors of the adult fovea are absent near birth because of the immaturity of foveal cones, develop by 24 months, and mature into childhood. This validates the source of SDOCT signal and provides a framework to assess foveal development and disease.

Histologic Development of the Human Fovea From Midgestation to Maturity

PURPOSE To describe the histologic development of the human central retina from fetal week (Fwk) 22 to 13 years. DESIGN Retrospective observational case series. METHODS Retinal layers and neuronal substructures were delineated on foveal sections of fixed tissue stained in azure II-methylene blue and on frozen sections immunolabeled for cone, rod, or glial proteins. Postmortem tissue was from 11 eyes at Fwk 20-27; 8 eyes at Fwk 28-37; 6 eyes at postnatal 1 day to 6 weeks; 3 eyes at 9 to 15 months; and 5 eyes at 28 months to 13 years. RESULTS At Fwk 20-22 the fovea could be identified by the presence of a single layer of cones in the outer nuclear layer. Immunolabeling detected synaptic proteins, cone and rod opsins, and Müller glial processes separating the photoreceptors. The foveal pit appeared at Fwk 25, involving progressive peripheral displacement of ganglion cell, inner plexiform, and inner nuclear layers. The pit became wider and shallower after birth, and appeared mature by 15 months. Between Fwk 25 and Fwk 38, all photoreceptors developed more distinct inner and outer segments, but these were longer on peripheral than foveal cones. After birth the foveal outer nuclear layer became much thicker as cone packing occurred. Cone packing and neuronal migration during pit formation combined to form long central photoreceptor axons, which changed the outer plexiform layer from a thin sheet of synaptic pedicles into the thickest layer in the central retina by 15 months. Foveal inner and outer segment length matched peripheral cones by 15 months and was 4 times longer by 13 years. CONCLUSIONS These data are necessary to understand the marked changes in human retina from late gestation to early adulthood. They provide qualitative and quantitative morphologic information required to interpret the changes in hyper- and hyporeflexive bands in pediatric spectral-domain optical coherence tomography images at the same ages.

Supraselective intra-arterial chemotherapy: evaluation of treatment-related complications in advanced retinoblastoma.

Purpose: The purpose of this study is to report the complication profile and safety evaluation of supraselective intra-arterial melphalan chemotherapy in children undergoing treatment with advanced retinoblastoma. Methods: Twelve eyes of 10 children with advanced retinoblastoma (Reese-Ellsworth Group Vb or International Classification Group D) were treated with supraselective intra-ophthalmic artery infusion of melphalan. Eleven eyes of nine children had previously failed traditional management with systemic chemotherapy and laser ablation and underwent intra-ophthalmic artery infusion of melphalan as an alternative to enucleation. Serial ophthalmic examinations, retinal photography, and ultrasonographic imaging were used to evaluate treatment regime. Results: Ophthalmic artery cannulation was successfully performed in 12 eyes of 10 patients (total 16 times). Striking regression of tumor, subretinal and vitreous seeds were seen early in each case. No severe systemic side effects occurred. Grade III neutropenia was seen in one patient. No transfusions were required. Three patients developed a vitreous hemorrhage obscuring tumor visualization. One patient developed periocular edema associated with inferior rectus muscle inflammation per orbital MRI. This same patient had scattered intraretinal hemorrhages and peripapillary cotton wool spots consistent with a Purtscher’s-like retinopathy that resolved spontaneously. At the 6-month follow-up examination, nine eyes had no evidence of tumor progression, whereas three eyes were enucleated for tumor progression. In each enucleated case, viable tumor was identified on histopathologic examination. Conclusions: Ophthalmic intra-arterial infusion with melphalan is an excellent globe-conserving treatment option in advanced retinoblastoma cases with minimal systemic side effects. Local toxicities include microemboli to the retina and choroid (1/12, 8%), vitreous hemorrhage (3/12, 25%), and myositis (1/12, 8%). Enucleation remained a definitive treatment for tumor progression in 3 of 12 eyes in this small case series with limited follow-up. Further studies are necessary to establish the role of supraselective intra-arterial melphalan chemotherapy for children with retinoblastoma.

Ultra high-resolution anterior segment optical coherence tomography in the evaluation of anterior corneal dystrophies and degenerations.

PURPOSE To evaluate the clinical usefulness of a spectral-domain ultra high-resolution anterior segment optical coherence tomography (UHR OCT) in examination, diagnosis, and management of various anterior corneal dystrophies and degenerations. DESIGN Noncomparative case series. PARTICIPANTS Fifty-nine eyes of 38 consecutive patients were enrolled in the study and included 28 eyes of 14 patients with anterior corneal dystrophies, 21 eyes of 19 patients with anterior corneal degenerations or neoplasia, and 10 eyes of 5 patients with normal corneas. METHODS Subjects were imaged using a novel custom-built UHR OCT. Images were used to evaluate and describe the characteristics of anterior corneal dystrophies and degenerations. Nineteen patients underwent surgical management, and those histopathologic specimens were analyzed and correlated with the UHR OCT images. MAIN OUTCOME MEASURES Comparison of clinical findings, UHR OCT images, and corresponding histopathologic specimens. RESULTS The UHR OCT provided clear delineation of corneal anatomic features and pathologic corneal deposits in most cases. The characteristics and depth of these deposits are illustrated and can be localized to specific layers of the cornea. When available, there was significant correlation between UHR OCT images and histopathologic features, providing a noninvasive confirmation of the clinical diagnosis. CONCLUSIONS Ultra high-resolution OCT is an innovative technique to perform in vivo optical biopsies and a promising research and clinical tool for the evaluation of corneal pathologic features in a noninvasive manner. The future use of this novel technology will evolve and increasingly is becoming a vital tool in the clinical and surgical management of corneal diseases.

Clinicopathologic review of enucleated eyes after intra-arterial chemotherapy with melphalan for advanced retinoblastoma.

change if the air had direct access to the venous circulatory system. The clinical situation is further complicated by a patent foramen ovale (which is present in 23%-45% of adults, based on autopsy studies). A patent foramen ovale allows trapped air to access the arterial circulatory system through the opening between the right and left atrium. This can result in air emboli throughout the systemic arterial circulatory system, causing cerebral, cardiac, and visceral infarction, as occurred in the second case. Treatment of VAE consists of immediately flooding the operative field with fluid to stop entry of the air. Additional measures would be at the discretion of the anesthesiologist and include increasing inspired oxygen, discontinuing nitrous oxide, if it is being used, inotropic support, and aspiration of air if a right atrial catheter has been placed. Although this complication is rare, ophthalmologists should be aware that it can occur during an air/fluid exchange, especially in the setting of significant trauma. During retinal cases, the anesthesiologist may not be fully aware of maneuvers happening within the eye, and the operating surgeon may be the first to recognize this problem if a patient becomes hemodynamically unstable after an air/fluid exchange is initiated. Promptly terminating the air infusion and returning the eye to a fluid filled state may help avoid systemic morbidity.

Delay in retinal photoreceptor development in very preterm compared to term infants.

PURPOSE We compared photoreceptor development from spectral domain optical coherence tomography (SD-OCT) imaging in very preterm infants (VPT, <32 weeks gestational age) with those of term infants. METHODS The microanatomy of foveal SD-OCT images obtained at the bedside at 37 to 42 weeks term equivalent postmenstrual age (TEA) was reviewed with qualitative and quantitative analysis of retinal and especially photoreceptor layers in the macula. Measures of maturity included presence of the cone outer segment tips (COST) or the ellipsoid zone (EZ) at foveal center, distance from Bruchs membrane (BM) to the EZ at the foveal center, and radial distance from foveal center to first appearance of the EZ. RESULTS The incidence of the EZ developed at the foveal center was lower in VPT infants (9/64, 14%) versus term infants (22/47, 47%, P < 0.001) and lower in VPT infants with macular edema (3/46) versus VPT without edema (6/18, P = 0.01). Mean ± SD distance from the foveal center to the visible EZ was 783 ± 440 μm in VPT, and 492 ± 501 μm in term infants, P = 0.002. The height of the BM-to-EZ at the foveal center did not differ in VPT versus term infants. The COST band was not visible in any infant. CONCLUSIONS Photoreceptor inner and outer segment development in VPT infants appears delayed when compared to term infants, and the photoreceptor RPE junction remains immature in all infants at TEA. Delayed maturation of photoreceptors could contribute to differences in visual function in some VPT infants.

Uveal Melanoma Treated With Iodine-125 Episcleral Plaque: An Analysis of Dose on Disease Control and Visual Outcomes

PURPOSE To investigate, in the treatment of uveal melanomas, how tumor control, radiation toxicity, and visual outcomes are affected by the radiation dose at the tumor apex. METHODS AND MATERIALS A retrospective review was performed to evaluate patients treated for uveal melanoma with (125)I plaques between 1988 and 2010. Radiation dose is reported as dose to tumor apex and dose to 5 mm. Primary endpoints included time to local failure, distant failure, and death. Secondary endpoints included eye preservation, visual acuity, and radiation-related complications. Univariate and multivariate analyses were performed to determine associations between radiation dose and the endpoint variables. RESULTS One hundred ninety patients with sufficient data to evaluate the endpoints were included. The 5-year local control rate was 91%. The 5-year distant metastases rate was 10%. The 5-year overall survival rate was 84%. There were no differences in outcome (local control, distant metastases, overall survival) when dose was stratified by apex dose quartile (<69 Gy, 69-81 Gy, 81-89 Gy, >89 Gy). However, increasing apex dose and dose to 5-mm depth were correlated with greater visual acuity loss (P=.02, P=.0006), worse final visual acuity (P=.02, P<.0001), and radiation complications (P<.0001, P=.0009). In addition, enucleation rates were worse with increasing quartiles of dose to 5 mm (P=.0001). CONCLUSIONS Doses at least as low as 69 Gy prescribed to the tumor apex achieve rates of local control, distant metastasis-free survival, and overall survival that are similar to radiation doses of 85 Gy to the tumor apex, but with improved visual outcomes.

In Vivo Morphologic Characteristics of Salzmann Nodular Degeneration With Ultra-High-Resolution Optical Coherence Tomography

PURPOSE To examine the in vivo morphologic properties of Salzmann nodular degeneration with ultra-high-resolution optical coherence tomography (OCT). DESIGN Interventional case series. METHODS SETTING Single-center academic practice. STUDY POPULATION Nineteen eyes of 12 patients with Salzmann nodular degeneration were recruited to participate in the study. OBSERVATIONAL PROCEDURE Subjects were imaged using novel, custom-built ultra-high-resolution OCT. Images were used to describe in vivo characteristics of subepithelial nodules. Morphometric measurements were made with custom-built software. Ultra-high-resolution OCT findings were compared with histopathologic findings in 3 patients. MAIN OUTCOME MEASURES Identifiable in vivo morphologic characteristics of Salzmann nodular degeneration with ultra-high-resolution OCT. RESULTS Ultra-high-resolution OCT images demonstrate intraepithelial fibrous nodules with epithelial thinning and corneal surface elevation. The Bowman layer could be differentiated in 9 of 12 patients. The difference between the mean thickness of epithelium above the nodule and the thickness of normal epithelium was statistically significant (P < .0001). The correlation between thickness of the epithelium and thickness of the nodule was statistically significant (r = -0.48; P < .0001). The correlation between thickness of the nodule and total surface thickness (thickness of the epithelium + thickness of the nodule) was statistically significant (r = 0.98; P < .0001). Ultra-high-resolution OCT findings were consistent with histopathologic results. CONCLUSIONS Ultra-high-resolution OCT can be used to noninvasively image the cornea in Salzmann nodular degeneration. This new imaging technique helps us to demonstrate different in vivo morphologic characteristics of Salzmann nodular degeneration.

VITAMIN D DEFICIENCY IN NEOVASCULAR VERSUS NONNEOVASCULAR AGE-RELATED MACULAR DEGENERATION

Purpose: To compare 25-hydroxyvitamin D (25OHD) levels in patients with neovascular age-related macular degeneration (NVAMD) with patients with nonneovascular age-related macular degeneration and control patients. Methods: Medical records of all patients diagnosed with age-related macular degeneration and tested for serum 25OHD level at a single medical center were reviewed. Control patients were selected from patients diagnosed with pseudophakia but without age-related macular degeneration. The lowest 25OHD level available for each patient was recorded. Results: Two hundred sixteen patients with nonneovascular age-related macular degeneration, 146 with NVAMD, and 100 non–age-related macular degeneration control patients were included. The levels of 25OHD (mean ± SD) were significantly lower in NVAMD patients (26.1 ± 14.4 ng/mL) versus nonneovascular age-related macular degeneration (31.5 ± 18.2 ng/mL, P = 0.003) and control (29.4 ± 10.1 ng/mL, P = 0.049) patients. The prevalence of vitamin D insufficiency (<30 ng/mL 25OHD), deficiency (<20 ng/mL), and severe deficiency (<10 ng/mL) were highest in the NVAMD group. The highest quintile of 25OHD was associated with a 0.35 (95% confidence interval, 0.18–0.68) odds ratio for NVAMD. Conclusion: This is the largest study to compare 25OHD levels in patients with the different clinical forms of age-related macular degeneration. Mean 25OHD levels were lower and vitamin D deficiency was more prevalent in NVAMD patients. These associations suggest that further research is necessary regarding vitamin D deficiency as a potentially modifiable risk factor for the development of NVAMD.

FUNCTIONAL OUTCOMES OF YOUNG INFANTS WITH AND WITHOUT MACULAR EDEMA.

Purpose: The authors relate posterior segment microanatomy from perinatal spectral domain optical coherence tomography to visual acuity, brain abnormalities, and neurodevelopment. Methods: Thirteen infants (11 preterm and 2 term birth), imaged in the nursery with portable spectral domain optical coherence tomography, had visual acuity and sensorimotor testing at age 9 months to 15 months (grating acuity) or 4 years to 5 years (optotype), and medical records reviewed for brain magnetic resonance imaging reports and Bayley scales testing at age 18 months to 24 months. Results: Eight children with age-appropriate macular microanatomy without edema on perinatal spectral domain optical coherence tomography had optimal (≥20/40) or within normal limits (grating acuity) visual acuity. Five children with perinatal macular edema had suboptimal visual acuity (in 9/10 eyes) and sensorimotor deficits, magnetic resonance imaging abnormalities, or poor neurodevelopment. Macular edema persisted in 1 infant through 9-month corrected age. Conclusion: Maturation of the visual system and evolution of retinal anomalies can be monitored with posterior segment spectral domain optical coherence tomography. Retinal microanatomy observed in infancy might relate to subsequent vision and other central nervous system events, but additional studies are needed to determine the range of normal microanatomy in infants and how this relates to vision and neurodevelopment.