Posterior Segment Eye Diseases Research Articles

Telemedicine for ophthalmic consultation services: use of a portable device and layering information for graders

Introduction We compared remote, image-based patient consultations to in-person consultations at emergency department and inpatient hospital settings. Methods Patients evaluated by the ophthalmic consultation services (gold standard) were imaged over a two-week period. A trained study coordinator took anterior segment photographs (AS) and posterior segment photographs (PS) with a portable camera (PictorPlus, Volk Optical, Cleveland, OH). Ophthalmologists (graders) determined photograph quality, presence of pathology, and their confidence in disease detection. At a separate session, graders reassessed photographs accompanied by a one-sentence summary of demographics and chief complaint (CHx). We computed accuracy and reliability statistics. Results We took AS photographs of 24 eyes of 15 patients and PS photographs of 39 eyes of 20 patients. The majority of images were rated as acceptable or excellent in quality (AS: 89–96%; PS: 70–75%). Graders detected AS pathology with 62–81% sensitivity based on photographs, increasing to 87–88% sensitivity with photographs plus CHx. Graders detected PS pathology with 79–86% sensitivity based on a photograph only, increasing to 100% sensitivity with photographs plus CHx. Discussion In this pilot study, there is evidence that portable ophthalmic imaging technologies could enable ophthalmologists to remotely evaluate anterior and posterior segment eye diseases with good sensitivity. The ophthalmologist could detect ocular pathology on photographs more accurately if they were provided brief clinical information.

PLGA Microparticles Entrapping Chitosan-Based Nanoparticles for the Ocular Delivery of Ranibizumab.

Age-related macular degeneration (AMD) is the leading cause of certified vision loss worldwide. The standard treatment for neovascular AMD involves repeated intravitreal injections of therapeutic proteins directed against vascular endothelial growth factor, such as ranibizumab. Biodegradable polymers, such as poly(lactic-co-glycolic acid) (PLGA), form delivery vehicles which can be used to treat posterior segment eye diseases, but suffer from poor protein loading and release. This work describes a "system-within-system", PLGA microparticles incorporating chitosan-based nanoparticles, for improved loading and sustained intravitreal delivery of ranibizumab. Chitosan-N-acetyl-l-cysteine (CNAC) was synthesized and its synthesis confirmed using FT-IR and (1)H NMR. Chitosan-based nanoparticles composed of CNAC, CNAC/tripolyphosphate (CNAC/TPP), chitosan, chitosan/TPP (chit/TPP), or chit/TPP-hyaluronic acid (chit/TPP-HA) were incorporated in PLGA microparticles using a modified w/o/w double emulsion method. Nanoparticles and final nanoparticles-within-microparticles were characterized for their protein-nanoparticle interaction, size, zeta potential, morphology, protein loading, stability, in vitro release, in vivo antiangiogenic activity, and effects on cell viability. The prepared nanoparticles were 17-350 nm in size and had zeta potentials of -1.4 to +12 mV. Microscopic imaging revealed spherical nanoparticles on the surface of PLGA microparticles for preparations containing chit/TPP, CNAC, and CNAC/TPP. Ranibizumab entrapment efficiency in the preparations varied between 13 and 69% and was highest for the PLGA microparticles containing CNAC nanoparticles. This preparation also showed the slowest release with no initial burst release compared to all other preparations. Incorporation of TPP to this formulation increased the rate of protein release and reduced entrapment efficiency. PLGA microparticles containing chit/TPP-HA showed the fastest and near-complete release of ranibizumab. All of the prepared empty particles showed no effect on cell viability up to a concentration of 12.5 mg/mL. Ranibizumab released from all preparations maintained its structural integrity and in vitro activity. The chit/TPP-HA preparation enhanced antiangiogenic activity and may provide a potential biocompatible platform for enhanced antiangiogenic activity in combination with ranibizumab. In conclusion, the PLGA microparticles containing CNAC nanoparticles showed significantly improved ranibizumab loading and release profile. This novel drug delivery system may have potential for improved intravitreal delivery of therapeutic proteins, thereby reducing the frequency, risk, and cost of burdensome intravitreal injections.

Automated screening system for retinal health using bi-dimensional empirical mode decomposition and integrated index

Posterior Segment Eye Diseases (PSED) namely Diabetic Retinopathy (DR), glaucoma and Age-related Macular Degeneration (AMD) are the prime causes of vision loss globally. Vision loss can be prevented, if these diseases are detected at an early stage. Structural abnormalities such as changes in cup-to-disc ratio, Hard Exudates (HE), drusen, Microaneurysms (MA), Cotton Wool Spots (CWS), Haemorrhages (HA), Geographic Atrophy (GA) and Choroidal Neovascularization (CNV) in PSED can be identified by manual examination of fundus images by clinicians. However, manual screening is labour-intensive, tiresome and time consuming. Hence, there is a need to automate the eye screening. In this work Bi-dimensional Empirical Mode Decomposition (BEMD) technique is used to decompose fundus images into 2D Intrinsic Mode Functions (IMFs) to capture variations in the pixels due to morphological changes. Further, various entropy namely Renyi, Fuzzy, Shannon, Vajda, Kapur and Yager and energy features are extracted from IMFs. These extracted features are ranked using Chernoff Bound and Bhattacharyya Distance (CBBD), Kullback–Leibler Divergence (KLD), Fuzzy-minimum Redundancy Maximum Relevance (FmRMR), Wilcoxon, Receiver Operating Characteristics Curve (ROC) and t-test methods. Further, these ranked features are fed to Support Vector Machine (SVM) classifier to classify normal and abnormal (DR, AMD and glaucoma) classes. The performance of the proposed eye screening system is evaluated using 800 (Normal=400 and Abnormal=400) digital fundus images and 10-fold cross validation method. Our proposed system automatically identifies normal and abnormal classes with an average accuracy of 88.63%, sensitivity of 86.25% and specificity of 91% using 17 optimal features ranked using CBBD and SVM-Radial Basis Function (RBF) classifier. Moreover, a novel Retinal Risk Index (RRI) is developed using two significant features to distinguish two classes using single number. Such a system helps to reduce eye screening time in polyclinics or community-based mass screening. They will refer the patients to main hospitals only if the diagnosis belong to the abnormal class. Hence, the main hospitals will not be unnecessarily crowded and doctors can devote their time for other urgent cases.

Gene Delivery by Subconjunctival Injection of Adenovirus in Rats: A Study of Local Distribution, Transgene Duration and Safety

Subconjunctival injection is a minimally invasive route for gene delivery to ocular tissues, but has traditionally been limited to use in the cornea. The accurate ocular distribution of virus has not, however, been previously investigated. Adenovirus is an attractive gene vector as it can deliver large genes and allow for short-term gene expression, but how safe it is when delivered via subconjunctival injection remains to be established. We have characterized the bio-distribution and safety of subconjunctivally administered adenovirus in Brown Norway rats. The bio-distribution and transgene duration of adenovirus carrying luciferase gene (Ad-Luci) at various time intervals were evaluated via bioluminescence imaging after subconjunctival injection. Adenovirus carrying a reporter gene, β-galactosidase (Ad-LacZ) or hrGFP (Ad-hrGFP) was administered subconjunctivally and the viral distribution in various ocular tissues was assessed by histological analysis and quantitative PCR (qPCR). Hepatic damage was assessed by biochemical and immunohistological analysis with TUNEL stain. Systemic immunogenicity was assessed by measuring serum level of TNF-α via ELISA, 2 hours and 14 days after administration of adenovirus. Retinal function was examined by electroretinography. Subconjunctival injection of Ad-Luci induced luciferase expression in the injected eyes within 24 hours, for at least 64 days. Histological analysis showed adenovirus distributed across anterior and posterior ocular tissues. qPCR demonstrated different amounts of adenovirus in different ocular tissues, with the highest amounts closest to the injection site Unlike the intravenous route, subconjunctivally delivered adenovirus did not elicit any detectable hepatic injury or systemic immunogenicity. Retinal function was unaffected by adenovirus irrespective of administration route. In conclusion, an adenoviral vector administered subconjunctivally can infiltrate into different ocular tissues and lead to short-term ocular transgene expression, without causing hepatic injury and immune activation. Therefore, subconjunctivally administered adenovirus may be a promising gene delivery approach for managing anterior and posterior segment eye diseases requiring short-term therapy.

Automated detection of age-related macular degeneration using empirical mode decomposition

Age-related Macular Degeneration (AMD) is the posterior segment eye disease affecting elderly people and may lead to loss of vision. AMD is diagnosed using clinical features like drusen, Geographic Atrophy (GA) and Choroidal NeoVascularization (CNV) present in the fundus image. It is mainly classified into dry and wet type. Dry AMD is most common among elderly people. At present there is no treatment available for dry AMD. Early diagnosis and treatment to the affected eye may reduce the progression of disease. Manual screening of fundus images is time consuming and subjective. Hence in this study we are proposing an Empirical Mode Decomposition (EMD)-based nonlinear feature extraction to characterize and classify normal and AMD fundus images. EMD is performed on 1D Radon Transform (RT) projections to generate different Intrinsic Mode Functions (IMF). Various nonlinear features are extracted from the IMFs. The dimensionality of the extracted features are reduced using Locality Sensitive Discriminant Analysis (LSDA). Then the reduced LSDA features are ranked using minimum Redundancy Maximum Relevance (mRMR), Kullback–Leibler Divergence (KLD) and Chernoff Bound and Bhattacharyya Distance (CBBD) techniques. Ranked LSDA components are sequentially fed to Support Vector Machine (SVM) classifier to discriminate normal and AMD classes. The performance of the current study is experimented using private and two public datasets namely Automated Retinal Image Analysis (ARIA) and STructured Analysis of the Retina (STARE). The 10-fold cross validation approach is used to evaluate the performance of the classifiers and obtained highest average classification accuracy of 100%, sensitivity of 100% and specificity of 100% for STARE dataset using only two ranked LSDA components. Our results reveal that the proposed system can be used as a decision support tool for clinicians for mass AMD screening.

Episcleral, Intrascleral, and Suprachoroidal Routes of Ocular Drug Delivery - Recent Research Advances and Patents

Subconjunctival/episcleral, intrascleral, and suprachoroidal routes of drug delivery for treatment of posterior segment eye diseases have become more feasible and popular in the past few years. These routes have the advantage of bypassing the main barriers to topical drug penetration, the ocular surface epithelium, the conjunctivallymphatics, and in the case of deep intrascleral and suprachoroidial delivery, the sclera barrier. Many ocular drug delivery application devices, drug delivery methods, and therapeutics that have been developed for intravitreal use can also be used subconjunctivally, intrasclerally, and in the suprachoroidal space. Alternatively, site-specific devices, such microneedles, and therapeutics, such as hydrogel matrices, have been developed to enhance ocular drug delivery. This manuscript will review the recent research advances and patents on episcleral, intrascleral, and suprachoroidal routes of ocular drug delivery.

Drug Delivery to the Back of the Eye Following Topical Administration: An Update on Research and Patenting Activity

Drug delivery to the back of the eye following topical administration remains an unmet need for the scientific community. Treatment of posterior segment diseases requires localized and long-term drug delivery to the retina, choroid, and Bruch's membrane. Until the last decade, there was limited evidence from large clinical trials that demonstrated the usefulness of pharmacotherapy compared to laser therapy or other vitreoretinal surgical techniques for the treatment of retinal diseases. This paradigm has shifted in recent years, with strong evidence demonstrating superior efficacy of ophthalmic drugs compared to previous gold standards. However, ophthalmologists are left with no options other than administering the therapeutics via implants and intravitreal injections, which are highly invasive and associated with patient non-compliance. A non-invasive topical therapy would enhance patient compliance and minimize the side-effects associated with intraocular implants and intravitreal injections. In an attempt to enhance patient compliance, the focus of research has shifted to the development of novel small molecule-based eye drop formulations. This review article discusses the relevant patents and summarizes the resurgence in the treatment of posterior segment eye diseases through topical drug administration.

Posterior segment eye disease in sub‐Saharan Africa: review of recent population‐based studies

ObjectiveTo assess the burden of posterior segment eye diseases (PSEDs) in sub-Saharan Africa (SSA).MethodsWe reviewed published population-based data from SSA and other relevant populations on the leading PSED, specifically glaucoma, diabetic retinopathy and age-related macular degeneration, as causes of blindness and visual impairment in adults. Data were extracted from population-based studies conducted in SSA and elsewhere where relevant.ResultsPSEDs, when grouped or as individual diseases, are a major contributor to blindness and visual impairment in SSA. PSED, grouped together, was usually the second leading cause of blindness after cataract, ranging as a proportion of blindness from 13 to 37%.ConclusionsPSEDs are likely to grow in importance as causes of visual impairment and blindness in SSA in the coming years as populations grow, age and become more urban in lifestyle. African-based cohort studies are required to help estimate present and future needs and plan services to prevent avoidable blindness.

Progress in sustained-release drug delivery system for treatment of posterior segment eye diseases

There is an urgent requirement to find effective therapeutic procedures for the treatment of refractory eye diseases of posterior segment such as posterior uveitis, proliferative vitreoretinopathy, and macular edema associated with diabetes and retinal vein occlusion. Due to systemic side effect developed from systemic drug administration and the low efficiency of topical drug administration, implantable drug devices for the treatment of posterior segment diseases have been explored. In recent years, three different intraocular implantable devices (ganciclovir, fluocinolone acetonide and dexamethasone) have been approved by FDA and showed exciting clinical efficacy. However, these devices have surgical complications and the drug-related side effects. Recently, transscleral drug delivery to the posterior segment has been investigated. Transscleral drug delivery has advantages of large scleral surface area, better safety profile, easily drug administration and could evolve into an effective route with the use of novel biomaterials and the study of drug delivery methods.

The Nakuru Posterior Segment Eye Disease Study: Methods and Prevalence of Blindness and Visual Impairment in Nakuru, Kenya

To estimate the prevalence of blindness and visual impairment (VI) in adults aged ≥50 years in the Nakuru district of Kenya and to identify sociodemographic risk factors for these conditions. We also sought to validate the Rapid Assessment of Avoidable Blindness (RAAB) methodology. There were 5010 subjects enumerated for this study. Of these, 4414 participants underwent examination, for a response rate of 88.1%. Cross-sectional, population-based survey. Cluster random samplings with probability proportionate to size procedures were used to select a representative cross-sectional sample of adults aged ≥50 years. Each participant was interviewed, had distance visual acuity (VA) measured with reduced logarithm of the minimal angle of resolution tumbling-E chart, underwent autorefraction, and thereby had measurements of presenting, uncorrected, and best-corrected VA. All participants, regardless of vision, underwent detailed ophthalmic examinations including slit-lamp assessment and dilated retinal photographs. Visual acuity of <6/12. A representative sample of 4414 adults were enumerated (response rate, 88.1%). The prevalence of blindness (VA < 3/60 in better eye) was 1.6% (95% confidence interval [CI], 1.2-2.1%) and of VI, 0.4% (95% CI, 0.3-0.7%); 8.1% (95% CI, 7.2-9.2%); and 5.1% (95% CI, 4.3-6.1%) were severely (<6/60-3/60), moderately (<6/18-6/60), or mildly (<6/12-6/18) visually impaired, respectively. Being male, having less education, having Kalenjin tribal origin, and being ≥80 years old were associated with increased blindness prevalence. Prevalence estimates were comparable to a RAAB performed in the same area 2 years earlier. This survey provides reliable estimates of blindness and VI prevalence in Nakuru. Older age and tribal origin were identified as predictors of these conditions. This survey validates the use of RAAB as a method of estimating blindness and VI prevalence.

A review of implantable intravitreal drug delivery technologies for the treatment of posterior segment eye diseases

Intravitreal implantable device technology utilizes engineered materials or devices that could revolutionize the treatment of posterior segment eye diseases by affording localized drug delivery, responding to and interacting with target sites to induce physiological responses while minimizing side‐effects. Conventional ophthalmic drug delivery systems such as topical eye‐drops, systemic drug administration or direct intravitreal injections do not provide adequate therapeutic drug concentrations that are essential for efficient recovery in posterior segment eye disease, due to limitations posed by the restrictive blood‐ocular barriers. This review focuses on various aspects of intravitreal drug delivery such as the impediment of the blood‐ocular barriers, the potential sites or intraocular drug delivery device implantation, the various approaches employed for ophthalmic drug delivery and includes a concise critical incursion into specialized intravitreal implantable technologies for the treatment of anterior and posterior segment eye disease. In addition, pertinent future challenges and opportunities in the development of intravitreal implantable devices is discussed and explores their application in clinical ophthalmic science to develop innovative therapeutic modalities for the treatment of various posterior segment eye diseases. The inherent structural and functional properties, the potential for providing rate‐modulated drug delivery to the posterior segment of the eye and specific development issues relating to various intravitreal implantable drug delivery devices are also expressed in this review. © 2009 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 2219–2239, 2010

In vitro transscleral iontophoresis of high molecular weight neutral compounds

The aim of the work was to study in vitro, across porcine and human sclera, the effect of transscleral iontophoresis on the permeation of high molecular weight neutral dextrans, chosen as models of high molecular weight drugs. Iontophoretic (anodal and cathodal) and passive permeation experiments were performed through pig sclera using acetaminophen (MW = 151 Da) and labelled dextrans (MW between 4.4 kDa and 120 kDa) as neutral model compounds. Anodal iontophoresis of 120 kDa dextran was also performed on human sclera. Membrane charge was also determined at different pH values. Both human and pig sclera show a net negative charge at pH 7.4 and in the presence of current an electroosmotic convective solvent flow in the anode-to-cathode direction takes place. During anodal iontophoresis, the electroosmotic flow (whose entity resulted approximately 4 μl cm −2 h −1) was able to increase 2–6.5 times the transscleral flux of dextrans. Transscleral iontophoresis can be useful for enhancing the transport across the sclera of high molecular weight compounds, even though neutral. This result suggests a possible application of this technique for the non-invasive administration of new biotech drugs for the treatment of the posterior segment eye diseases.

Scleral Permeability of a Small, Single-Stranded Oligonucleotide

Developing more effective ocular drug delivery systems is essential to improving the treatment of posterior segment eye disease. The large target area provided by the sclera and potentially less vision threatening complications are advantages of transscleral administration compared to more traditional modalities of drug delivery to the posterior segment. We aimed to determine the permeability coefficient for the in vitro diffusion of a small, single-stranded, oligonucleotide across human sclera. Transscleral permeability was measured by placing 100 microL of 2.96 x 10(-4) mol single-stranded, fluorescein-labeled oligonucleotide (MW = 7998.3) on the episcleral surface of sclera mounted in a perfusion chamber. Fractions of choroidal perfusate were collected hourly for 24 hours. The permeability constant or K(trans) for the transscleral diffusion of the naked, single-stranded, fluorescein-labeled oligonucleotide was 7.67 +/- 1.8 x 10(-7) cm/s (mean +/- SEM, N = 7). The permeability constant or K(trans) after intrascleral injection of the same fluorescein-labeled oligonucleotide was 1.32 +/- 0.42 x 10(-7) (mean +/- SEM, N = 4). This analysis demonstrates that diffusion of a naked, 24-base, single-stranded, fluorescein-labeled oligonucleotide can be accomplished by both of the described methods. The ability to deliver single-stranded oligonucleotides across the sclera may prove to be advantageous given the development of several novel therapeutic strategies that use similar molecules.

Growth factors in retinal diseases: Proliferative vitreoretinopathy, proliferative diabetic retinopathy, and retinal degeneration

The goal of this review is to present the current knowledge on specific growth factor involvement in posterior segment eye disease. Growth factors can be defined as multifunctional signals which modify cell growth or proliferation, alone or in concert, by binding to specific cell surface receptors. Their biological effects on cells include cell adhesion, migration, survival, differentiation, extracellular matrix secretion, protease and protease inhibitor release, production of other growth activities, and angiogenesis. Growth factors couple the cell to the microenvironment. As some growth factors are soluble mediators of wound repair and angiogenesis, it seems possible that proliferative vitreoretinopathy and proliferative diabetic retinopathy are caused or aggravated by these factors. Other factors act as survival factors and can possibly prevent retinal degeneration. The multifunctional nature of growth factors makes it probable that practical uses will be found for these agents in the future.

Ivermectin Treatment of Patients with Severe Ocular Onchocerciasis

The treatment of onchocerciasis with diethylcarbamazine and suramin is associated with an exacerbation of ocular disease. This occurs more frequently in patients with severe onchocercal ocular disease. We assessed ocular changes following ivermectin treatment in 39 patients with severe ocular onchocerciasis. Patients were treated with 100, 150, or 200 micrograms/kg of ivermectin at either 1 or 2 year intervals and followed for 3 years. There was no evidence for an acute exacerbation of either anterior or posterior segment eye disease, and there was a marked improvement in ocular status in the group as a whole. There was a significant decrease in onchocercal involvement which was maintained for at least 3 years. Annual treatment with ivermectin can be used safely in patients with severe ocular disease and is beneficial over a prolonged period of time.