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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

PET/CT imaging of I-124-radiolabeled bevacizumab and ranibizumab after intravitreal injection in a rabbit model.

PURPOSE: To determine whether bevacizumab and ranibizumab remain confined within the vitreous cavity after intravitreal injection and to determine the pharmacokinetic properties of these agents within the vitreous cavity. METHODS: Radiolabeling with I-124 was completed using a modified Iodogen method. After testing for radiochemical purity, three anesthetized Dutch-belted rabbits underwent intravitreal injection with I-124 bevacizumab, and three underwent it with I-124 ranibizumab. All rabbits were imaged with a Micro PET-CT scanner on days 0, 2, 5, 7, 14, 21, 28, and 35. RESULTS: The intravitreally placed radiolabeled agents were found to be contained within the vitreous cavity for the duration of the study with no extravasation into the central nervous system or elsewhere. I-124 bevacizumab was detectable until day 28, whereas I-124 ranibizumab was detectable until day 21. The kinetic model appears to represent a two-compartment model, and the average retention times for bevacizumab and ranibizumab after correction for radioactive decay were found to be 4.2 days and 2.8 days, respectively. CONCLUSIONS: There was no significant escape of bevacizumab and ranibizumab from the vitreous cavity after intravitreal injection. After correction for radioactive decay, both agents remained detectable until 28 and 21 days, respectively, with retention properties that validated those methods reported in previous studies.

Volume of visual field assessed with kinetic perimetry and its application to static perimetry.

BACKGROUND: The purpose of this study was to quantify the volume of the kinetic visual field with a single unit that accounts for visual field area and differential luminance sensitivity. METHODS: Kinetic visual field perimetry was performed with a Goldmann perimeter using I4e, I3e, I2e, and I1e targets. The visual fields of 25 normal volunteers (17 women, eight men) of mean age 33.9 ± 10.1 (range 17-64) years were obtained and digitized. Isopter areas were measured with a method devised to correct cartographic distortion due to polar projection inherent in perimetry and are expressed in steradians. The third dimension of each isopter represents sensitivity to target luminance and was calculated as log (target luminance(-1)). If luminance is expressed in cd/m(2), the values for the third dimension are 0.5 for I4e, 1.0 for I3e, 1.5 for I2e, and 2.0 for I1e. The resulting unit is a steradian (log 10(3) (cd/m(2))(-1) which is referred to as a Goldmann. In addition, the visual fields of four patients with representative visual defect patterns were examined and compared with normal subjects. RESULTS: Mean isopter areas for normal subjects were 3.092 ± 0.242 steradians for I4e, 2.349 ± 0.280 steradians for I3e, 1.242 ± 0.263 steradians for I2e, and 0.251 ± 0.114 steradians for the I1e target. Isopter volumes were 1.546 ± 0.121 Goldmanns for the I4e target, 1.174 ± 0.140 Goldmanns for I3e, 0.621 ± 0.131 Goldmanns for I2e, and 0.126 ± 0.057 Goldmanns for I1e. The total mean visual field volume in our study for the I target was 3.467 ± 0.371 Goldmanns. CONCLUSION: The volume of the island of vision may be used to quantify a visual field with a single value which contains information about both visual field extension and differential luminance sensitivity. This technique may be used to assess the progression or stability of visual field defects over time. A similar method may be applied to static perimetry.

Age related macular degeneration and visual disability.

Age-related macular degeneration (AMD) is the leading cause of central blindness or low vision among the elderly in industrialized countries. AMD is caused by a combination of genetic and environmental factors. Among modifiable environmental risk factors, cigarette smoking has been associated with both the dry and wet forms of AMD and may increase the likelihood of worsening pre-existing AMD. Despite advances, the treatment of AMD has limitations and affected patients are often referred for low vision rehabilitation to help them cope with their remaining eyesight. The characteristic visual impairment for both forms of AMD is loss of central vision (central scotoma). This loss results in severe difficulties with reading that may be only partly compensated by magnifying glasses or screen-projection devices. The loss of central vision associated with the disease has a profound impact on patient quality of life. With progressive central visual loss, patients lose their ability to perform the more complex activities of daily living. Common vision aids include low vision filters, magnifiers, telescopes and electronic aids. Low vision rehabilitation (LVR) is a new subspecialty emerging from the traditional fields of ophthalmology, optometry, occupational therapy, and sociology, with an ever-increasing impact on the usual concepts of research, education, and services for visually impaired patients. Relatively few ophthalmologists practise LVR and fewer still routinely use prismatic image relocation (IR) in AMD patients. IR is a method of stabilizing oculomotor functions with the purpose of promoting better function of preferred retinal loci (PRLs). The aim of vision rehabilitation therapy consists in the achievement of techniques designed to improve PRL usage. The use of PRLs to compensate for diseased foveae has offered hope to these patients in regaining some function. However, in a recently published meta-analysis, prism spectacles were found to be unlikely to be of substantial benefit in people with age-related macular degeneration. Prescription filters are one of the most beneficial visual aids that people with macular degeneration. In principle, one aims both at reducing short-wavelength light to reduce glare and at identifying light with specific wavelengths (colours) preferred by the patient for viewing. In both instances, such interventions result in apparent improved contrast sensitivity and better visual acuity. Although specific tests are performed to determine the best colour, tint, lens material, and type of frame for the patient's need, no scientific protocol has been developed so far to assist in prescribing tinted or selective transmission lenses . Magnifying optical lenses are available in a wide range of dioptric powers and are made from materials that correct for weight (plastic), thickness (high index), spherical aberrations (aspherical), and variable light intensities (photochromatic). These lenses can be used as loose lenses, mounted on optical frames, or used with a wide variety of attachments. As the dioptric power of plus lenses increases, the viewing distance of the target decreases, hence their usefulness mainly for tasks requiring near resolution acuity, like reading. Magnification can also be achieved with the use of telescopic devices that are built of two or more plus and (or) minus (minifying) optical lenses. Normal resolution acuity levels can be achieved with these devices for all viewing distances. Therefore, all telescopic devices are useful only for stationary patient tasks that do not require mobility and orientation. Electronic magnification has the great advantage over plus lenses of producing an acuity reserve enabling reading skills for almost all levels of visual acuity. The additional benefit provided is preservation of binocularity, even at high levels of visual disparity between the two eyes. Vision rehabilitation can help patients to maximize their remaining vision and adapt to activities of daily living. The support of the patient's social network is critical to patient's well-being as patients adjust to being partially sighted.