Smoking as a risk factor for choroidal neovascularization secondary to presumed ocular histoplasmosis syndrome.

PURPOSE: To investigate the relationship of smoking to choroidal neovascularization (CNV) secondary to presumed ocular histoplasmosis syndrome (POHS). DESIGN: Retrospective, case-control study. PARTICIPANTS: A total of 568 patients 18 to 50 years of age, 142 of whom were diagnosed with CNV secondary to POHS in a private retina practice between July 1, 2000, and August 1, 2010. Four hundred twenty-six were controls selected from a private comprehensive ophthalmology practice at the same location. METHODS: A retrospective medical record review was performed for all participants. Age, gender, zip code, CNV diagnosis date, insurance status, and smoking status at CNV diagnosis date were collected first for the POHS patients. For each of these 142 patients, 3 randomly selected comprehensive clinic patients, whose visit date fell within 3 months of the corresponding POHS patient's CNV diagnosis date, served as controls. Age, gender, zip code, visit date, reason for visit, insurance type, and smoking status were recorded. Descriptive statistics were calculated for cases and controls. MAIN OUTCOME MEASURES: Logistic regression analyses were performed for both univariate and multivariate models, with CNV secondary to POHS as the main outcome variable and smoking as the main predictor variable, while adjusting for age, gender, insurance type, median household income, and education level. RESULTS: The mean age of patients with CNV secondary to POHS was 39.0±7.1 years, whereas that of the control patients was 35.7±9.1 years. Of the patients with CNV secondary to POHS, 47.2% were current or former smokers (42.3% current, 4.9% former). Of the control patients, 22.5% were current or former smokers (21.8% current, 0.7% former). Age, insurance type, median income, educational attainment, and smoking status were significant in the univariate models. In the final adjusted logistic regression model, only age (odds ratio [OR], 1.04; 95% confidence interval [CI], 1.02-1.07; P = 0.001), level of educational attainment by zip code (OR, 0.95; 95% CI, 0.92-0.98; P = 0.001) and smoking status (OR, 2.83; 95% CI, 1.86-4.31; P<0.0001) were significant. CONCLUSIONS: The odds of a smoker having CNV secondary to POHS are almost 3 times that of a nonsmoker. In this study, the odds of having CNV secondary to POHS increased with age and decreased with increasing level of educational attainment.

A prospective trial of infliximab therapy for refractory uveitis: preliminary safety and efficacy outcomes.

OBJECTIVE: Infliximab, a monoclonal antibody against tumor necrosis factor alpha, is approved by the US Food and Drug Administration for treatment of numerous autoimmune disorders. We conducted a prospective, open-label phase 2 clinical trial to assess the effectiveness of infliximab in treating refractory autoimmune uveitis. METHODS: We prospectively enrolled 23 patients from the uveitis clinic of the Casey Eye Institute, Portland, Ore, into this trial. All patients meeting eligibility criteria received 3 infliximab infusions at weeks 0, 2, and 6. Clinical success was ascertained at week 10. Patients meeting initial criteria for success received an infusion at week 14 and every 8 weeks thereafter, with dose escalation permitted for breakthrough inflammation, and underwent outcome measurements at week 50. RESULTS: All patients underwent outcome assessment at week 10. Eighteen (78%) of these subjects met criteria for clinical success at this time. Success was judged by the composite clinical end point of visual acuity, control of intraocular inflammation, ability to taper concomitant medication therapy, and improvement in inflammatory signs on fluorescein angiography and/or ocular coherence tomography. Successful grading required improvement in at least 1 of 4 subcomponents and worsening in none. Seven of 14 patients enrolled for 1 year continued infliximab therapy and maintained their successful grading. Five did not complete 1 year of treatment because of significant adverse events, and 2 terminated treatment early for reasons unrelated to the study. Serious adverse events that were potentially related to infliximab included pulmonary embolus, congestive heart failure, lupus-like reaction in 2, and vitreous hemorrhage in 2 patients. Antinuclear antibodies developed in 15 of 20 enrolled patients receiving 3 or more infusions. CONCLUSIONS: Infliximab was an effective short-term immunosuppressive agent in most of the patients, with 18 of 23 meeting criteria for clinical success at week 10. Infliximab was effective in the long term in all patients able to complete 50 weeks of therapy. Although some patients achieved clear benefit, the rate of serious toxic effects was unexpectedly high. Further long-term studies are warranted to determine the safety and efficacy of infliximab in treating intraocular inflammation.

Treatment of corticosteroid dependent optic neuropathy with intravenous immunoglobulin.

PURPOSE: To report a patient with corticosteroid dependent optic neuropathy treated with intravenous immunoglobulin (IVIg). DESIGN: Interventional case report. METHODS: Records review. RESULTS: A 25-year-old woman developed bilateral vision loss with pain on eye movement in association with disk edema, dilated retinal veins, and hemorrhage. The vision improved markedly with prednisone, but she required a minimum of 20 mg/d despite concomitant therapy with methotrexate, cyclosporine, and/or mycophenolate mofetil. IVIg, 0.5 g/kg/d for 3 days each month with subsequent reduction in frequency, allowed discontinuation of all immunosuppression. CONCLUSIONS: Corticosteroid dependent optic neuropathy was successfully treated with IVIg.

Leber congenital amaurosis associated with optic disk neovascularization and vitreous hemorrhage.

PURPOSE: To report an unusual case of optic disk neovascularization and vitreous hemorrhage associated with Leber congenital amaurosis (LCA). DESIGN: Interventional case report. METHODS: A 16-year-old Caucasian girl with a history of LCA presented with decreased vision in her left eye, diffuse retinal pigmentary abnormalities characteristic of LCA, and hemorrhage over the left optic disk and macula. Six months of follow-up revealed optic disk neovascularization. A small amount of neovascularization was noted in the right eye at 6 months. RESULTS: An extensive systemic evaluation indicated no other cause for the neovascularization. Panretinal photocoagulation was performed in both eyes, and subsequently the neovascularization regressed. CONCLUSIONS: Leber congenital amaurosis like retinitis pigmentosa, can rarely be associated with neovascularization of the disk, which is amenable to treatment with peripheral photocoagulation if it does not spontaneously regress.

With a mere nod, uveitis enters a new era.

PURPOSE: To advance the knowledge of the ophthalmologist with regard to new developments in the genetics and pathologic mechanisms of uveitis. DESIGN: A review of recently published literature exploring the relationship between the nucleotide oligomerization domain (NOD2) gene and uveitis. RESULTS: Mutations in the nucleotide-binding region of NOD2 were found to be responsible for familial juvenile systemic granulomatosis (Blau syndrome or Jabs disease), a rare form of uveitis, arthritis, and dermatitis. The NOD2 gene is thought to be involved in the innate immune response to pathogens. Currently, the pathologic mechanisms behind Blau syndrome in familial juvenile systemic granulomatosis are unknown, but the interactions of NOD2 with caspases, nuclear factor kappaB, and other pathways are slowly being revealed. CONCLUSIONS: A single amino acid change in NOD2 can lead to a chronic granulomatous uveitis. By studying NOD2 and the proteins that interact with NOD2, we should gain a better understanding of the pathogenic mechanisms of uveitis and identify novel ways to halt its destructive consequences.

Novel approaches for retinal drug delivery.

Novel methods of ophthalmic drug delivery are being developed to facilitate treatment of a variety of eye diseases. Pharmaceuticals administered intravitreally are able to bypass the blood-ocular barrier to achieve constant therapeutic levels in the eye, while minimizing systemic side effects. Sustained-release intravitreal implants are being developed to enhance further the intravitreal route of administration. Liposomes, microscopic vesicles with a membrane-like lipid bilayer surrounding an aqueous compartment, are being developed to incorporate a wide variety of drug molecules, proteins, nucleotides, and even plasmids giving them great potential for use in ophthalmology. Biodegradable scleral plugs containing pharmaceuticals have the advantage of biodegradability and the ability to fit in a relatively small diameter of 1 mm. Conjugate drugs, which are covalently linked, decrease drug solubility, which increases their half-life and also limits the amount of active drug present at a given time. Viral vectors have been investigated in the delivery of genetic material to the posterior segment of the eye. Retrovirus, adenovirus, adenoma-associated virus, herpes virus, and lentivirus have been investigated for gene transfer to the retina. Finally, iontophoresis, a method of drug delivery typically involving the application of low electric currents to drive molecules across barriers, such as skin, is being explored for ophthalmic applications.

Genetics of uveitis.

Uveitis phenotypes can differ substantially, and most uveitis diseases are considered polygenic with complex inheritance patterns. When considering the genetics of these diseases, common threads can be identified. For example, in virtually every polygenic disease studied, there exists an HLA genetic association. This association can be strong, such as the associations of HLA-B27 with AAU and HLA-A29 with BSCR; or it can be more subtle, involving several HLA genes or a combination of HLA genes that compose specific haplotypes. In many of these conditions, it is hypothesized that genes other than classic MHC genes but located at the MHC locus may be important susceptibility genes. Genome-wide scans and other genetic methods are becoming increasingly successful in identifying genetic loci and candidate genes in many inflammatory disorders that have an uveitic component. It will be important to test these findings as uveitis-specific genetic factors. Therefore, the burgeoning understanding of the human genome promises to result in new insight into the pathogenesis of uveitis.

Treatment of retinal and choroidal degenerations and dystrophies: current status and prospects for gene-based therapy.

Inherited retinal and choroidal degenerations account for a significant portion of blindness in children and young adults. This article reviews the current status and future prospects for the treatment of these disorders. Current treatment strategies include nutritional intervention for gyrate atrophy of the choroid and retina with hyperornithinemia, abetalipoproteinemia, and Refsum's disease, as well as vitamin A supplementation for retinitis pigmentosa. Future therapeutic prospects include gene therapy for both recessive and dominant disease, secondary gene-based therapies, such as pharmaceutic gene product replacement and treatment with survival factors, anti-apoptotic agents, and calcium blockers, and, finally, stem cell therapy.

Effects of twice-daily topical difluprednate 0.05% emulsion in a child with pars planitis.

PURPOSE: To report the effects of twice-daily difluprednate in a child with pars planitis (PP). DESIGN/METHODS: Case report. RESULTS: PP was controlled with topical difluprednate for 1 year. Then an atypical pattern of steroid response--delayed, relatively sudden onset of recalcitrant ocular hypertension (OHT)--and posterior subcapsular cataract (PSC) formation necessitated alternative treatment. CONCLUSION: Although not a standard treatment, in select cases of PP topical difluprednate therapy could be a useful short-term treatment option while alternative treatments are considered or immunosuppressive agents build to therapeutic levels. Ophthalmologists must be aware of the potential for delayed onset of serious complications when using difluprednate.

A unique case of autoimmune retinopathy associated with anti-alpha-enolase antibodies.

Background. We report a case of autoimmune retinopathy associated with anti-alpha-enolase antibodies with unique manifestations. Methods. A case report. Results. A 30-year-old male experienced recurrent, primarily peripheral visual field disturbances and minimal photopsia, with interval symptom resolution. Fundus changes subsequently developed in areas corresponding to the previous visual field symptoms. Electroretinogram showed bilaterally symmetric abnormalities of light-adapted responses and suggested loss of photoreceptor function. Only anti-alpha-enolase antibodies were detected on Western blot. Our patient noted cutaneous symptoms at the time of both episodes of visual symptoms, but not in the interim. Biomicroscopy revealed subtle small reddish spots in areas of the peripheral retina corresponding to the areas of the patient's visual field where he noted symptoms. To our knowledge these reddish spots have not been reported in autoimmune retinopathy and may clinically support in vitro and in vivo evidence that anti-alpha-enolase antibodies may target photoreceptors. Conclusions. Our patient demonstrates some unique features adding to the known characteristics of autoimmune retinopathy associated with anti-alpha-enolase antibodies. As more cases are reported, further understanding of the features and pathophysiology of this rare condition will hopefully be elucidated.

Radial optic neurotomy for central retinal vein occlusion: 117 consecutive cases.

PURPOSE: Venous occlusive disease is the second leading cause of permanent retinal vascular blindness. The anatomy of the optic disk including the cribriform plate and scleral ring may contribute to the development of retinal vasoocclusive diseases. Neurovascular compression within the confined space at this location (scleral outlet) may play a pathoetiologic role in central retinal vein occlusion (CRVO). We developed a surgical procedure (radial optic neurotomy [RON]) to open this space and relieve pressure on the central retinal vein. METHODS: Pars plana vitrectomy with RON was performed on 117 consecutive patients with CRVO and severe loss of vision (defined as 20/200 or worse). Patients were observed with serial fundus photography, fluorescein angiography, determination of Snellen visual acuity, and biomicroscopy for anterior segment neovascularization. RESULTS: There were no serious complications noted with this procedure. Anatomical and clinical improvement as determined by fundus examination, fundus photography, and fluorescein angiography was found in 95% of patients. Snellen visual acuity improved by an average of 2.5 lines (range, 1-12 lines) in 71% of patients. Two or more lines were gained in 53% of patients, and > or = 4 lines were gained in 25%. Anterior segment neovascularization was found in 6% of patients with CRVO. CONCLUSIONS: Surgical decompression of CRVO via RON is a technically feasible and safe procedure that was associated with anatomical resolution of CRVO in 95% patients and improved visual function in 71%.

Radial optic neurotomy with adjunctive intraocular triamcinolone for central retinal vein occlusion: 63 consecutive cases.

PURPOSE: Central retinal vein occlusion (CRVO) is a leading cause of permanent retinal vascular blindness. In a previous communication the authors reported the results of radial optic neurotomy (RON) in 117 consecutive patients with severe CRVO. Persistent cystoid macular edema (CME) and macular pigmentation (MP) were observed and correlated with worse macular function. Intraocular triamcinolone (IOK) has been used to treat patients with CME and CRVO. The authors performed RON with simultaneous, adjunctive IOK (RON/IOK) in patients with CRVO to ascertain any anatomic or visual benefit of this combined approach. METHODS: Pars plana vitrectomy and RON were performed on a case-by-case basis on 63 consecutive patients with CRVO and visual acuity of 20/200 or worse. At the end of the case, 4 mg of triamcinolone was injected into the vitreous cavity (RON/IOK). Patients were observed with serial fundus photographs, fluorescein angiography (FA), Snellen visual acuity (VA), intraocular pressures (IOP), and biomicroscopy for anterior segment neovascularization (ANV). Anatomic and visual outcomes were compared to a previous series of 117 patients with severe CRVO undergoing RON alone. RESULTS: Clinical improvement as determined by fundus examination, photography, and FA was noted in 93% of patients following RON/IOK. Snellen VA improved by an average of three lines (range one to seven) in 68% of all patients. Two or more lines were gained in 44% of patients and four or more lines were gained in 20% of patients. ANV developed in 7% of patients following RON/IOK. Persistent CME and MP were noted in 17% and 28% of patients, respectively. These outcomes were similar to patients undergoing RON alone without IOK. Elevated IOP was noted in 25% of patients and one patient developed endophthalmitis following RON/IOK. CONCLUSIONS: Surgical decompression of CRVO via RON/IOK is a technically feasible procedure. Clinical resolution of the CRVO and improved visual function noted in RON/IOK paralleled outcomes following RON alone. RON/IOK was associated with a higher incidence of elevated IOP and endophthalmitis.

Laser trabecular sclerosis for chronic hypotony after vitreoretinal surgery.

PURPOSE: To perform a pilot study of laser trabecular sclerosis (LTS) for chronic ocular hypotony after vitreoretinal surgery. DESIGN: Prospective noncomparative case series. PARTICIPANTS: Three patients with chronic hypotony after vitreoretinal procedures underwent LTS. All patients had undergone complex vitreoretinal surgery with attached retinas postoperatively but with persistent hypotony and poor vision. INTERVENTION: Laser trabecular sclerosis was performed in a fashion similar to laser trabeculoplasty, using a 100-microm spot, 800 to 1000 mW power at 0.1 seconds, and applying heavy confluent treatment in >/=1 sessions throughout the angle where trabecular meshwork was visible. MAIN OUTCOME MEASURES: Intraocular pressure (IOP), best spectacle-corrected visual acuity, and complications were studied. RESULTS: In 1 patient, a single session of LTS was followed by an increase in IOP of approximately 4 mm, with subjective and objective improvement in vision. A second patient exhibited improvement in IOP and visual acuity after 3 sessions of LTS. A third patient underwent 3 sessions of LTS without improvement in IOP or vision. CONCLUSION: Given the limitations of this small series, including the lack of a randomized prospective design, it is not possible to determine the safety or efficacy of LTS, but this study does suggest that this procedure could play a therapeutic role in some patients with chronic symptomatic hypotony after complex intraocular surgery. Further study is warranted.

Electroretinographic and clinicopathologic correlations of retinal dysfunction in infantile neuronal ceroid lipofuscinosis (infantile Batten disease).

Infantile neuronal ceroid lipofuscinosis (INCL) is an autosomal recessive disease that results from deficiency of palmitoyl-protein thioesterase-1 (PPT1). INCL leads to retinal blindness, neurodegeneration, and early death. We studied the clinical features and electroretinogram (ERG) in three patients and histopathologic and immunofluorescence analyses of the retina in the third patient, who died at 3 years 2 months of age. The ERGs for the 2 youngest patients (ages 1.7 and 2.3 years) showed normal scotopic bright flash a-wave amplitudes with severe loss of b-wave (electronegative ERG), indicating dysfunction at or proximal to the photoreceptor inner segments. The third patient at 2.9 years of age showed subnormal a-wave amplitudes and even greater loss of b-wave amplitudes. Histopathology revealed reduced cell numbers in all retinal layers, including the inner nuclear layer (INL), and a central epiretinal membrane. Autofluorescent lipofuscin granules were present in all neuronal cell types in the retina. Cones and rods in the parafoveal area were labeled with a cone cytoplasmic marker, mAb 7G6, and anti-rhodopsin, respectively, and had extremely short outer segments. The periphery showed better preservation but photoreceptor outer segments were short. Immunofluorescence revealed degenerate rods and cones throughout the retina with better preservation in the periphery. Autofluorescent lipofuscin was found in all cell types, including cone inner segments, to a greater degree than seen in normal ageing. The ERG findings support the existence early in the disease of a relative pre- or post-synaptic block of effective neurotransmission from photoreceptor inner segments to the second order bipolar neurons.