Dynamic Contrast-Enhanced Magnetic Resonance Imaging of Ocular Melanoma as a Tool to Predict Metastatic Potential.

PURPOSE: This study explores the capability of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to differentiate tumor characteristics of metastatic and nonmetastatic choroidal melanoma as a potential tool for patient management. MATERIALS AND METHODS: A total of 13 patients (69 ± 9 years) with choroidal melanoma were imaged using DCE-MRI on a 3-T MRI system with a 16-channel head coil. The Tofts 2-compartment model was chosen for quantification, and parameters K (the transfer constant from the blood plasma to the extracellular space) and Kep (the transfer constant from the extracellular space to the blood plasma) were calculated and compared. Metastasis was excluded by subsequent clinical work-up or confirmed by histology after targeted biopsy. RESULTS: Six patients were diagnosed with metastatic melanoma and 7 without. All orbital tumors were at least larger than 2 mm. A significant difference was identified in K between patients with (0.73 ± 0.18/min) and without (1.00 ± 0.21/min) metastatic melanoma (P = 0.03), whereas the difference was not significantly shown in Kep (2.58 ± 1.54/min of metastatic patients vs 2.98 ± 1.83/min of nonmetastatic patients, P = 0.67). CONCLUSIONS: Dynamic contrast-enhanced magnetic resonance imaging has the potential to differentiate orbital melanomas with metastatic and nonmetastatic spread. Thus, DCE-MRI has the potential to be an in vivo imaging technique to predict early which patients are prone to metastatic disease.

Retrobulbar vasculature using 7-T magnetic resonance imaging with dedicated eye surface coil.

PURPOSE: To determine the resolution and utility of using a dedicated, single-loop eye coil at 7 T to image the posterior ocular structures and vascular anatomy. METHODS: Imaging was performed on eight subjects (age range 26-54 years, four female, four male) with 7 T using a transmit head coil for excitation and a dedicated 5-cm eye surface receive coil. Acquisition parameters at 7 T for 3D spoiled gradient echo (3D-SPGR) sequences were optimized. RESULTS: It was possible to delineate the retina, sclera, and choroid, and fine details within the anterior and posterior segments of the eye. Retro-orbital and posterior ocular anatomy remained well visualized despite motion and susceptibility artifacts of anterior ocular structures. The ophthalmic arteries and their first-order branches were consistently visualized and improved with registration and summation of repeat scans. Furthermore, the central retinal vessels could be visualized. Intravenous gadolinium contrast reagent did not noticeably improve image quality. CONCLUSIONS: High-resolution 7-T MRI with a dedicated eye coil can provide unique high-resolution noninvasive images of retro-orbital and posterior ocular structural and vascular anatomy and is able to resolve structures as small as the central retina vein.

Anatomic and pharmacokinetic properties of intravitreal bevacizumab and ranibizumab after vitrectomy and lensectomy.

PURPOSE: To determine the anatomic characteristics and pharmacokinetic properties of intravitreally placed bevacizumab and ranibizumab after pars plana lensectomy or pars plana vitrectomy and to compare these with nonoperated control eyes in a rabbit model. METHODS: Three groups of six Dutch-belted rabbits each underwent pars plana vitrectomy, pars plana lensectomy, or served as nonsurgical controls. Twelve days after surgery, 3 rabbits from each group underwent intravitreal injection in one eye with 1.25 mg/0.05 mL I-124-bevacizumab or 0.5 mg/0.05 mL I-124-ranibizumab. Serial imaging with integrated positron emission and computed tomography (PET/CT) were obtained on Days 0, 2, 5, 7, 14, 21, 28, and 35. Measured radioactivity emission in becquerels/milliliter was used to calculate the half-lives for each agent. RESULTS: The intravitreally placed radiolabeled agents were contained within the vitreous cavity for the duration of the study. The average clearance half-lives with standard error for bevacizumab and ranibizumab after correction for radioactive decay were, respectively, 4.22 ± 0.07 days and 2.81 ± 0.05 days in unoperated eyes, 2.30 ± 0.09 days (P < 0.0001) and 2.13 ± 0.05 days (P < 0.0001) after vitrectomy, and 2.08 ± 0.07 days (P = 0.0001) and 1.79 ± 0.05 days (P < 0.0001) after lensectomy. CONCLUSION: Intravitreal retention was longer for bevacizumab than ranibizumab within all study groups and was significantly reduced after vitrectomy and lensectomy for both agents. Consideration for more frequent intravitreal anti-vascular endothelial growth factor dosing regimens may be made for patients whose treated eyes have undergone previous vitrectomy or who are aphakic.

Vitreous inflammation associated with intravitreal anti-VEGF pharmacotherapy.

Vascular endothelial growth factor (VEGF) is a potent promoter of angiogenesis involved in a wide variety of physiologic processes. Intravitreal injections targeting VEGF have transformed the treatment of neovascular retinal diseases. Currently, there are four anti-VEGF agents in use: bevacizumab, ranibizumab, pegaptanib, and aflibercept. The success and frequency of anti-VEGF therapy have made the ocular safety profile of these agents of vital importance. This paper focuses on sterile endophthalmitis. In this paper, we compare the incidences of posttreatment sterile endophthalmitis among the four agents, review the mechanism of actions, and discuss the most prevalent hypotheses leading to sterile endophthalmitis.

Advances in Ophthalmic Epigenetics and Implications for Epigenetic Therapies: A Review.

The epigenome represents a vast molecular apparatus that writes, reads, and erases chemical modifications to the DNA and histone code without changing the DNA base-pair sequence itself. Recent advances in molecular sequencing technology have revealed that epigenetic chromatin marks directly mediate critical events in retinal development, aging, and degeneration. Epigenetic signaling regulates retinal progenitor (RPC) cell cycle exit during retinal laminar development, giving rise to retinal ganglion cells (RGCs), amacrine cells, horizontal cells, bipolar cells, photoreceptors, and Müller glia. Age-related epigenetic changes such as DNA methylation in the retina and optic nerve are accelerated in pathogenic conditions such as glaucoma and macular degeneration, but reversing these epigenetic marks may represent a novel therapeutic target. Epigenetic writers also integrate environmental signals such as hypoxia, inflammation, and hyperglycemia in complex retinal conditions such as diabetic retinopathy (DR) and choroidal neovascularization (CNV). Histone deacetylase (HDAC) inhibitors protect against apoptosis and photoreceptor degeneration in animal models of retinitis pigmentosa (RP). The epigenome represents an intriguing therapeutic target for age-, genetic-, and neovascular-related retinal diseases, though more work is needed before advancement to clinical trials.

Intraocular Methotrexate for the Treatment and Prevention of Proliferative Vitreoretinopathy: A Review.

Purpose: To review the current literature on the use of intravitreal methotrexate (IVT MTX) for the treatment and prevention of proliferative vitreoretinopathy (PVR). Methods: All reports of IVT MTX to treat and prevent PVR published in PubMed, Google Scholar, and EBSCOhost were reviewed. The relevant current studies are included in this report. Results: The literature search yielded 32 articles describing the use of MTX in PVR. These included preclinical studies, 1 case report, and several case series. Early studies found that IVT MTX is a promising medication for the treatment and prevention of PVR. MTX works as a potent anti-inflammatory agent through a new mechanism of action different from that of other medications for use in PVR. Few side effects have been reported and were mostly limited to mild reversible corneal keratopathy. There are 2 current ongoing randomized controlled clinical trials to further evaluate the efficacy of MTX for PVR. Conclusions: MTX is a safe and potentially efficacious medication for the treatment and prevention of PVR. Additional clinical trials are needed to further establish this effect.

Systemic treatment of vitreous inflammation.

Non infectious vitreous inflammation is often vision threatening and can be associated with potentially life-threatening systemic conditions. Treatment is often challenging as it involves systemic medications that can be associated with adverse effects. The classes of drugs are ever expanding and include corticosteroids, antimetabolites, alkylating agents, T-cell and calcineurin agents, biologic agents, and interferons. Each class of systemic therapy for non-infectious vitreous inflammation is reviewed. We discuss the mechanisms of action, usual clinical dosages, the specific conditions that are treated, the adverse effects, and usual course of treatment for each class of therapy.

Intravitreal devices for the treatment of vitreous inflammation.

The eye is a well-suited organ for local delivery of therapeutics to treat vitreous inflammation as well as other pathologic conditions that induce visual loss. Several conditions are particularly challenging to treat and often require chronic courses of therapy. The use of implantable intravitreal devices for drug delivery is an emerging field in the treatment of vitreous inflammation as well as other ophthalmologic diseases. There are unique challenges in the design of these devices which include implants, polymers, and micro- and nanoparticles. This paper reviews current and investigational drug delivery systems for treating vitreous inflammation as well as other pathologic conditions that induce visual loss. The use of nonbiodegradable devices such as polyvinyl alcohol-ethylene vinyl acetate polymers and polysulfone capillary fibers, and biodegradable devices such as polylactic acid, polyglycolic acid, and polylactic-co-glycolic acid, polycaprolactones, and polyanhydrides are reviewed. Clinically used implantable devices for therapeutic agents including ganciclovir, fluocinolone acetonide, triamcinolone acetonide, and dexamethasone are described. Finally, recently developed investigational particulate drug delivery systems in the form of liposomes, microspheres, and nanoparticles are examined.

Ocriplasmin: who is the best candidate?

Enzymatic vitreolysis is currently the focus of attention around the world for treating vitreomacular traction and full-thickness macular hole. Induction of posterior vitreous detachment is an active area of developmental clinical and basic research. Despite exerting an incompletely elucidated physiological effect, ocriplasmin (also known as microplasmin) has been recognized to serve as a well-tolerated intravitreal injection for the treatment of vitreomacular traction and full-thickness macular hole. There are several unexplored areas of intervention where enzymatic vitreolysis could potentially be used (ie, diabetic macular edema). Recent promising studies have included combinations of enzymatic approaches and new synthetic molecules that induce complete posterior vitreous detachment as well as antiangiogenesis. Although no guidelines have been proposed for the use of ocriplasmin, this review attempts to aid physicians in answering the most important question, "Who is the best candidate?"

Epiretinal membrane: optical coherence tomography-based diagnosis and classification.

Epiretinal membrane (ERM) is a disorder of the vitreomacular interface characterized by symptoms of decreased visual acuity and metamorphopsia. The diagnosis and classification of ERM has traditionally been based on clinical examination findings. However, modern optical coherence tomography (OCT) has proven to be more sensitive than clinical examination for the diagnosis of ERM. Furthermore, OCT-derived findings, such as central foveal thickness and inner segment ellipsoid band integrity, have shown clinical relevance in the setting of ERM. To date, no OCT-based ERM classification scheme has been widely accepted for use in clinical practice and investigation. Herein, we review the pathogenesis, diagnosis, and classification of ERMs and propose an OCT-based ERM classification system.

The Vitreomacular Interface in Diabetic Retinopathy.

Diabetic retinopathy (DR) is a leading health concern and a major cause of blindness. DR can be complicated by scar tissue formation, macular edema, and tractional retinal detachment. Optical coherence tomography has found that patients with DR often have diffuse retinal thickening, cystoid macular edema, posterior hyaloid traction, and tractional retinal detachment. Newer imaging techniques can even detect fine tangential folds and serous macular detachment. The interplay of the vitreous and the retina in the progression of DR involves multiple chemokine and other regulatory factors including VEGF. Understanding the cells infiltrating pathologic membranes at the vitreomacular interface has opened up the possibility of new targets for pharmacotherapy. Vitrectomies for DR remain a vital tool to help relieve tension on the macula by removing membranes, improving edema absorption, and eliminating the scaffold for new membrane formation. Newer treatments such as triamcinolone acetonide and VEGF inhibitors have become essential as a rapid way to control DR at the vitreomacular interface, improve macular edema, and reduce retinal neovascularization. These treatments alone, and in conjunction with PRP, help to prevent worsening of the VMI in patients with DR.

In vivo rabbit eyecup preparation for use in retinal research.

PURPOSE: To develop an in vivo rabbit eyecup preparation that preserves neuronal and vascular connections with normal posterior segment contour, permitting direct access to the retina and facilitating retinal microsurgical and neuroscience research. METHODS: Cyanoacrylate glue was applied to the anterior sclera of six Dutch-belted rabbits before open-sky vitrectomy. The glue was used to harden the compliant scleral wall and to fix it to the surrounding periorbital tissues. RESULTS: A normal contour of the posterior segment was retained in all cases. Vitrectomy under air was successfully accomplished and an extensive removal of the vitreous gel was achieved. Fluorescein angiography revealed normal vascular patency of the retinal vessels after vitrectomy. CONCLUSIONS: The proposed modification of the rabbit eyecup retains the normal neurovascular connections and configuration of the retina, making it suitable for retinal microsurgical maneuvers or any procedures in which easy access to anatomically undisturbed retina is required.

Resolution of leukemic retinopathy following treatment with imatinib mesylate for chronic myelogenous leukemia.

PURPOSE: To report a case of leukemic retinopathy before and after treatment with imatinib mesylate (formerly STI-571) for chronic myelogenous leukemia (CML). DESIGN: Interventional case report. METHODS: A 58-year-old man diagnosed with stable phase CML (SP-CML) presented with blurry vision. Fundoscopy revealed several flame-shaped hemorrhages in the macular region in both eyes. One month after this initial visit, imatinib therapy was initiated. RESULTS: : The patient noticed improvement in his visual as well as his medical symptoms; on repeat examination 6 months after the initial visit, the retinal hemorrhages had resolved and remained so after 18 months. CONCLUSIONS: Imatinib appears to be an effective treatment for SP-CML, and the improvement in visual and medical symptoms in our case report correlates with this.

CT characteristics of intraocular perfluoro-N-octane.

Perfluoro-N-octane (PFO) is a heavy liquid that is used as an aid for complicated retinal surgical procedures. Although PFO is usually removed intraoperatively, the radiographic appearance of retained PFO may mimic an intraocular foreign body or vitreous hemorrhage. As the use of PFO in retinal procedures has become more widespread, recognition of its imaging appearance has become important in the differential diagnosis of intraocular foreign body and ocular trauma.

The effect of intravitreal bevacizumab and ranibizumab on cutaneous tensile strength during wound healing.

PURPOSE: To investigate the effect of intravitreal bevacizumab and ranibizumab on wound tension and by histopathology during cutaneous wound healing in a rabbit model and to compare this effect to placebo intravitreal saline controls 1 and 2 weeks following intravitreal injection. METHODS: A total of 120 New Zealand white rabbits were randomly assigned to one of three treatment groups each consisting of 40 rabbits. Each group received intravitreal injections of bevacizumab, ranibizumab, or normal saline. Immediately afterwards, each rabbit underwent four 6 mm full-thickness dermatologic punch biopsies. Twenty rabbits from each agent group underwent wound harvesting on day 7 or day 14. The skin samples were stained for CD34 for vascular endothelial cells on day 7, and maximal wound tensile load was measured on days 7 and 14. Quantitative assessment of mean neovascularization (MNV) scores was obtained from 10 contiguous biopsy margin 400× fields of CD34-stained sections by two independent observers. RESULTS: Wound tension reading means (N) with standard error and adjusted P-values on day 7 were: saline placebos, 7.46 ± 0.87; bevacizumab, 4.50 ± 0.88 (P = 0.041); and ranibizumab, 4.67 ± 0.84 (P = 0.025). On day 14 these were: saline placebos, 7.34 ± 0.55; bevacizumab, 6.05 ± 0.54 (P = 0.18); and ranibizumab 7.99 ± 0.54 (P = 0.40). MNV scores in CD34 stained sections were: saline controls, 18.31 ± 0.43; bevacizumab, 11.02 ± 0.45 (P < 0.0001); and ranibizumab, 13.55 ± 0.43 (P < 0.0001). The interobserver correlation coefficient was 0.928. CONCLUSION: At day 7, both anti-vascular endothelial growth factor (anti-VEGF) agents had significantly suppressed MNV scores and exerted a significant reduction of cutaneous wound tensile strength compared with saline controls. At day 14, neither agent produced a significant effect on tensile wound strength. Since angiogenesis is an integral component of the proliferative phase of wound healing, we encourage clinicians to be aware of their patients' recent surgical history during intravitreal anti-VEGF therapy and to consider refraining from their use during the perioperative period.

Serum levels of intravitreal bevacizumab after vitrectomy, lensectomy and non-surgical controls.

PURPOSE: To determine serum level differences of intravitreally-placed bevacizumab after vitrectomy and lensectomy-vitrectomy and to compare these with non-operated eyes in a rabbit model. METHODS: Five Dutch-belted rabbits underwent pars plana vitrectomy (PPV), five rabbits underwent pars plana lensectomy (PPL) and five rabbits served as non-surgical controls. Twelve days following the surgical procedures, each operated eye underwent an intravitreal injection consisting of 1.25 mg/0.05 mL bevacizumab. Serum levels from each rabbit were drawn on days 2, 4, 7, 10, 14, 21, 28 and 35 and were measured with ELISA immunoassay. RESULTS: The average peak serum concentration (Cmax) was highest for the PPL group (11.33 µg ± 3.48 mL), and was similar between the PPV (5.35 µg ± 2.69 mL) and non-surgical control groups (5.35 µg ± 0.69 mL). The average time to maximal plasma concentration (Tmax) in days was earliest for the PPL group (2.8 ± 0.47), followed by the PPV (5.6 ± 0.84) and non-surgical control groups (6.4 ± 0.71). The PPL group had higher serum levels than the other two groups until day 7 that was significant only at day 2 (p < 0.0001). After day 4, there were no significant differences or trends between any of the three groups. The half-life (T1/2) was fastest for the PPL group (1.41 ± 0.21 d) followed by the PPV (2.80 ± 3.35 d) and non-surgical control groups (6.69 ± 10.4 d). CONCLUSIONS: Serum bevacizumab levels were initially elevated following lensectomy and vitrectomy compared to non-surgical eyes following intravitreal injection. The half-life of bevacizumab was prolonged in non-surgical eyes presumably due to a slower release from the vitreous cavity.

Histopathology of optic nerve pit-associated maculopathy.

PURPOSE: To describe the histopathologic findings of an eye bank specimen containing an optic nerve pit with associated serous elevation of the macula and cavernous atrophy of the optic nerve. METHODS: An eye bank specimen found to have an optic nerve pit with serous elevation of the macula was grossly examined and photographed. The globe was processed for both light and scanning electron microscopy. RESULTS: The scanning electron microscopic study of this eye with an optic nerve pit revealed holes in the diaphanous membrane overlying the nerve at the edge of the optic pit. Serial histopathology sections revealed a connection between the holes overlying the optic pit and the subretinal space via a schisis-like cavity in the retina. CONCLUSION: The discovery of an optic nerve pit with coexisting serous detachment of the macula in an eye bank eye and subsequent pathological evaluation provides support for current theories into the mechanism of the visual loss in this condition. Our finding supports syneretic vitreous to be the source of the subretinal fluid.

Cytomegalovirus retinitis after central retinal vein occlusion in a patient on systemic immunosuppression: does venooclusive disease predispose to cytomegalovirus retinitis in patients already at risk?

Cytomegalovirus (CMV) retinitis remains the most common opportunistic ocular infection in immunocompromised patients. Patients with immunocompromising diseases, such as acquired immunodeficiency syndrome, inherited immunodeficiency states, malignancies, and those on systemic immunosuppressive therapy, are known to be at risk. Recently, it has been suggested that patients undergoing intravitreal injection of immunosuppressive agents may also be predisposed. One previous case report speculated that there may be an additional risk for CMV retinitis in acquired immunodeficiency syndrome patients with venoocclusive disease. This case study presents a case of CMV retinitis following central retinal vein occlusion in a patient on systemic immunosuppressants.

Pharmacokinetic properties of intravitreal I-124-aflibercept in a rabbit model using PET/CT.

PURPOSE: To determine the anatomic characteristics and pharmacokinetic properties of intravitreally-placed aflibercept in a rabbit model. MATERIALS AND METHODS: Four Dutch-belted rabbits underwent intravitreal injection with I-124-aflibercept. Serial imaging with PET/CT imaging was performed on days 0, 2, 5, 7, 14, 21, 28 and 35. Measured radioactivity emission in becquerels/mL was used to calculate the half-lives for aflibercept. RESULTS: I-124 aflibercept was confined within the vitreous cavity for the duration of the study. I-124 aflibercept could be detected in the vitreous cavity until day 28 and the average retention time with standard error after correction for radioactive decay was 4.58 ± 0.07 days. CONCLUSIONS: I-124 aflibercept was only visible in the vitreous cavity by PET/CT imaging following intravitreal injection. The retention properties were found to be comparable to those measured by other reported methods.