Metabolic control and diabetic retinopathy.

The Early Treatment Diabetic Retinopathy Study (ETDRS) identified important risk factors for progression to high risk proliferative diabetic retinopathy (PDR) including retinopathy severity, decreased visual acuity, and high levels of hemoglobin A1C (HbA1c). Additional risk factors for progression to PDR are decreased hematocrit and increased serum lipids. The long-term benefit of improving glycemic control was evaluated by three large studies: the Diabetes Control and Complications Trial (DCCT), the Stockholm Interventional Study, and the UK prospective study. Several small studies, notably the Kuwamoto study, also evaluated the relationship between the glycemic control and diabetic retinopathy. Intensive glycemic control reduces the risk of any retinopathy by approximately 27%. Intensive therapy is most effective when initiated early in the course of the diabetes, demonstrating a beneficial effect over the course and progression of retinopathy. The long term benefits of the intensive glycemic control greatly outweigh the risk of "early worsening." Lowering elevated serum lipid levels has been shown to decrease the risk of cardiovascular morbidity. The ETDRS data suggest that lipid lowering may also decrease the risk of hard exudate formation and associated vision loss in patients with diabetic retinopathy. Preservation of vision may be an additional motivating factor for lowering serum lipid levels in persons with diabetic retinopathy and elevated serum lipid levels.

Diabetic retinopathy and angiogenesis.

Diabetic retinopathy, a secondary microvascular complication of diabetes mellitus is the leading cause of blindness in the Unites States amongst individuals age 20 to 64. Two major retinal problems cause most of the diabetes-related vision loss: diabetic macular edema and complications from abnormal retinal blood vessel growth, angiogenesis. Secondary to angiogenesis, increased retinal blood flow is of pathogenic importance in the progression of diabetic retinopathy. Understanding the role of hyperglycemia seems to be the most critical factor in regulating retinal blood flow, as increased levels of blood glucose are thought to have a structural and physiological effect on retinal capillaries causing them to be both functionally and anatomically incompetent. High blood glucose induces hypoxia in retinal tissues, thus leading to the production of VEGF-A (vascular endothelial growth factor protein). Hypoxia is a key regulator of VEGF-induced ocular neovascularization. Secondary to the induction of VEGF by hypoxia, angiogenesis can be controlled by angiogenic inducers and inhibitors. The balance between VEGF and angiogenic inhibitors may determine the proliferation of angiogenesis in diabetic retinopathy. Since VEGF-A is a powerful angiogenic inducer, utilizing anti-VEGF treatments has proved to be a successful protocol in the treatment of proliferative diabetic retinopathy.

Ranibizumab for diabetic retinopathy.

Ranibizumab (Lucentis) is a Fab-Antibody with high affinity for VEGF, and is being designed to bind to all VEGF isoforms. This quality makes it a powerful drug for VEGF inhibition. Diseases of retinal and choroidal blood vessels are the most prevalent causes of moderate and severe vision loss in developed countries. Vascular endothelial growth factor plays a critical role in the pathogenesis of many of these diseases. Results of the pilot studies showed that intraocular injections of ranibizumab (Lucentis) decrease the mean retinal thickness and improve the BCVA in all the subjects. Proliferative diabetic retinopathy, currently treated with destructive laser photocoagulation, represents another potential target for anti-VEGF therapy. The early experience in animal models with proliferative retinopathy and neovascular glaucoma shows that posterior and anterior neovascularizations are very sensitive to anti-VEGF therapy. The outcome of two phase III clinical trials will increase our knowledge of the role of Lucentis in the treatment of DME.

Ischemic optic neuropathy.

Ischemic optic neuropathies (IONs) are the most frequent acute optic neuropathy in patients older than 50 years. They are classified according to the location of the ischemic damage into anterior ION and posterior ION. Ischemic optic neuropathies may also be categorized based on the presence or absence of temporal arteritis as an underlying etiology. Anterior ION presents with sudden, painless visual loss developing over hours to days. Examination findings usually include decreased visual acuity, a visual field defect, color vision loss, a relative afferent pupillary defect, and a swollen optic nerve head. Posterior ION occurs in arteritic, nonarteritic, and surgical settings. It is characterized by acute vision loss without initial disc edema but with subsequent optic disc atrophy.

Novel mutations in FRMD7 in X-linked congenital nystagmus. Mutation in brief #963. Online.

Congenital nystagmus is an eye movement disorder in which one or both eyes are in constant movement. It can be associated with a number of ocular or neurological diseases, or it can be inherited in an autosomal or X-linked fashion. The latter form is called idiopathic or motor nystagmus (CIN). Loci on the X chromosome (NYS1) and on 6p12 (NYS2), 7p11.2 (NYS3), and 13q31-q33 (NYS4) have been identified for CIN. The molecular characterization of NYS1 has recently been solved by Tarpey et al., who identified mutations in FRMD7, a gene of unclear function. We report five novel mutations in FRMD7 and confirm the role of this gene in the pathogenesis of X-linked congenital nystagmus.

Neurite outgrowth in retinal ganglion cell culture.

Retinal ganglion cells (RGC) are the projection neurons of the eye. The RGC is the primary cell type injured in a variety of diseases of the optic nerve, including glaucoma and optic neuritis. The most well-established extrinsic signal of RGC survival and axonal outgrowth is the neurotrophin brain-derived neurotrophic factor. An immunopurification system has been adapted in order to filter large enough quantities of RGCs from the mixed population of retinal neurons in order to perform high-throughput screening in a 96-well format. Using this assay, the screening of a combinatorial chemical library for compounds with a similar effect to brain-derived neurotrophic factor may be preformed. Follow-up validation studies are performed by evaluating for a dose-response relationship.

A system for inducible gene expression in retinal ganglion cells.

PURPOSE: To develop a system for inducible gene expression in retinal ganglion cells, Thy1 and ckit promoters were used to direct expression of a second-generation reverse tetracycline transactivator (rtTA2S-M2). METHODS: Transgenic mice were generated that harbor rtTA2S-M2 under the control of either the Thy1 or ckit promoter. These animals were crossed with mice transgenic for the LacZ gene downstream of a cassette of tet operator (TRE) binding sites. Induction of the LacZ reporter gene in vivo after either oral or subcutaneous doxycycline administration and in vitro in cultured retinal cells was assessed. To examine induction of a secreted protein, expression of pigment epithelium-derived factor (PEDF) in mice harboring Thy1-rtTA and TRE-PEDF constructs was quantified. RESULTS: Five of seven Thy1-rtTA lines showed induction with subcutaneous doxycycline: maximum induction in one line (Thy1-C), moderate in one line (Thy1-F), and minimal in three lines. There was no detectable retinal LacZ expression in the ckit-rtTA lines, despite expression of the ckit-rtTA transgene at the RNA level. In Thy1-rtTA lines, LacZ reporter expression as measured by X-gal staining was evenly dispersed throughout all quadrants of the retina, present in a subpopulation of retinal ganglion cell (RGC) bodies, RGC axons projecting through the retina and optic nerve, and some cells in the inner nuclear layer. Immunostaining for beta-galactosidase demonstrated more uniform expression in RGCs and cells of the inner aspect of the inner nuclear layer, which, by double staining with anti-beta-galactosidase and anti-calretinin antibodies, were consistent with amacrine cells. More than 95% of Thy-1 antigen-positive cells in the retina expressed the induced transgene. Subcutaneous doxycycline resulted in a more robust induction of LacZ than did oral administration. In vitro, the number of cells induced in culture increased in a dose-dependent manner, with maximum expression at 10 microg/mL at a level 3.4-fold over background. Thy1-rtTA/TRE-PEDF mice treated with doxycycline had 1000-fold induction in their retinal PEDF expression in comparison with nontransgenic mice and 600-fold induction over noninduced Thy1-rtTA/TRE-PEDF mice. CONCLUSIONS: A transgenic system for inducible RGC expression has been developed that demonstrates minimal leakiness and significant induction with doxycycline. This system will be useful for several applications.

Bone morphogenetic proteins promote neurite outgrowth in retinal ganglion cells.

PURPOSE: The purpose of the present study is to test the ability of members of the transforming growth factor/bone morphogenetic protein family to influence retinal ganglion cell (RGC) survival and neurite outgrowth in primary cell culture using a high throughput analysis. METHODS: Primary cell cultures were generated using immunoselection of Thy-1 positive cells from dissociated postnatal rat retina and grown on poly-L-lysine/laminin coated 96 well culture dishes in the presence or absence of members of the transforming growth factor/bone morphogenetic protein family. High throughput analysis was performed following fluorescence staining with Hoechst, Calcein AM, and TOTO-3. Outcomes included overall cell survival, survival of cells with neurite outgrowth, and a variety of parameters of neurite outgrowth. RESULTS: Immunomagnetic selection led to an enrichment of cell cultures for RGCs (79%+/-6.8%). While no significant effect on overall survival was observed with any of the factors tested, members of the bone morphogenetic protein (BMPs) family (BMP2, BMP13, and GDF8 (growth differentiation factor 8)) and BDNF (brain derived neurotrophic factor) increased the number of surviving RGCs with neurite extension in a dose dependent manner. As a group, BMPs increased the number of neurites, length of neurites, and the number of branch points, while BDNF primarily increased neurite length and branch points. CONCLUSIONS: We have developed an efficient system that allows for high throughput analysis of cultures enriched for RGCs. Using this assay system, we found that BMPs promote the survival of outgrowth neurons and neurite development in RGC culture.

Optic neuropathies caused by toxins and adverse drug reactions.

Toxic optic neuropathy refers to the ingestion of a toxin or an adverse drug reaction that results in vision loss from optic nerve damage. Patients may present with bilateral sudden loss of vision in the setting of an acute intoxication or an insidious asymmetric loss of vision from an adverse drug reaction. Toxins and drugs associated with a toxic optic neuropathy may directly harm the optic nerve; however, some drugs are associated with an ischemic optic neuropathy or optic neuritis, in which optic nerve damage is an indirect effect of the causative agent. The most important aspect of treatment is recognition and drug withdrawal. Patients need to be appropriately counseled, particularly in the setting of amiodarone-associated optic neuropathy.

Positron emission tomography scanning in essential blepharospasm.

PURPOSE: To localize in the brain using positron emission tomography neuroimaging with (18)fluorodeoxyglucose [PET ((18)FDG)] differences in glucose metabolism between patients with essential blepharospasm (EB) and controls. DESIGN: Prospective case-control study. METHODS: Positron emission tomography neuroimaging with (18)fluorodeoxyglucose was performed in 11 patients with EB and 11 controls matched for age and gender. Global analysis of images was used to localize differences in glucose metabolism between groups. RESULTS: Multiple cortical and subcortical abnormalities were observed in EB patients in comparison with controls. Cortical areas with the largest and most significant clusters of increased glucose uptake were the inferior frontal gyri, right posterior cingulate gyrus, left middle occipital gyrus, fusiform gyrus of the right temporal lobe, and left anterior cingulate gyrus. Cortical areas with the largest and most significant clusters of decreased glucose uptake were the inferior frontal gyri, ventral to the area of increased glucose metabolism. Subcortical abnormalities, consisting of increased glucose uptake, involved the right caudate and consisting of decreased glucose uptake, involved the left inferior cerebellar hemisphere and thalamus. CONCLUSIONS: Global analysis of positron emission tomography neuroimaging with (18)fluorodeoxyglucose neuroimaging in EB patients in comparison with controls demonstrates a pattern of abnormalities involving several cortical and subcortical areas that control blinking, including the inferior frontal lobe, caudate, thalamus, and cerebellum.

Survey of genetic neuro-ophthalmic disorders.

This article provides an overview of the genetic aspects of neuro-ophthalmic disorders. Leber's hereditary optic neuropathy, optic nerve hypoplasia, Duane's retraction syndrome, congenital nystagmus, and other disorders of neuro-ophthalmic interest are discussed.

Optic neuritis after anthrax vaccination.

OBJECTIVE: To report the occurrence of optic neuritis after anthrax vaccination in two patients. DESIGN: Observational case reports, review of literature. METHODS: Description of clinical history, examination, neuroimaging, and further studies in two patients experiencing optic neuritis in temporal association with anthrax vaccination. MAIN OUTCOME MEASURES: Visual acuity, visual fields. RESULTS: Two patients, 39 and 23 years of age, were seen with acute optic neuritis 1 month and 2 weeks, respectively, after anthrax booster vaccination and successfully treated with intravenous methylprednisolone. The first patient had a typical presentation and course of unilateral retrobulbar optic neuritis with excellent visual recovery. The second patient had a bilateral anterior optic neuritis and has required chronic immunosuppression to maintain his vision. Retinal and optic nerve autoantibodies were present in the second patient. No cross-reactive epitopes between anthrax vaccine and retina/optic nerve were identified. CONCLUSION: Optic neuritis is a potential adverse reaction of anthrax vaccination.