Imaging Biomarkers and Their Impact on Therapeutic Decision-Making in the Management of Neovascular Age-Related Macular Degeneration.

These recommendations, produced by a group of Canadian retina experts, have been developed to assist both retina specialists and general ophthalmologists in the management of vision-threatening neovascular age-related macular degeneration (nAMD). The recommendations are based on published evidence as well as collective experience and expertise in routine clinical practice. We provide an update on practice principles for optimal patient care, focusing on identified imaging biomarkers, in particular retinal fluid, as well as current and emerging therapeutic approaches. Algorithms for delivering high-quality care and improving long-term patient outcomes are provided, with an emphasis on timely and appropriate treatment to preserve and maintain vision. In the context of nAMD, increasing macular fluid or leakage on fluorescein angiography (FA) may indicate disease activity regardless of its location. Early elimination of intraretinal fluid (IRF) is of particular relevance as it is a prognostic indicator of worse visual outcomes. Robust referral pathways for second opinion and peer-to-peer consultations must be in place for cases not responding to intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy.

The many faces of ocular syphilis: case-based update on recognition, diagnosis, and treatment.

In recent years, syphilis (Treponema pallidum) has become increasingly prevalent in Canada, and as a result, rates of ocular syphilis are also rising. Classically, syphilis was seen primarily in men who have sex with men; now, it is increasingly seen in people of all age groups, sexes, and sexual orientations. We present a series of 26 cases of ocular syphilis from London, Ontario, 5 of which are discussed in detail to illustrate the varied presentations and diagnostic challenges of ocular syphilis. The presentations include uveitis, iris granuloma (gumma), retinitis (acute syphilitic posterior placoid chorioretinitis), vasculitis, optic neuritis, and serous retinal detachment. The 5 cases are mostly middle-aged heterosexual men and women without the typical risk factors that would alert the examiner to suspect syphilis. We emphasize the importance of testing for syphilis when assessing and treating inflammatory eye disease, regardless of demographics and known risk factors, given the increasing prevalence of this disease. Diagnosis of syphilis relies on serologic testing, which is complex and has undergone significant changes from historical reliance on the Venereal Disease Research Laboratory test. We provide an overview of the strategy and rationale for modern serologic testing. The mainstay of treatment remains intravenous penicillin G, with alternative antibiotics (e.g., ceftriaxone) being less effective.

Real-world assessment of intravitreal dexamethasone implant (0.7 mg) in patients with macular edema: the CHROME study.

BACKGROUND: The purpose of this study was to evaluate the real-world use, efficacy, and safety of one or more dexamethasone intravitreal implant(s) 0.7 mg (DEX implant) in patients with macular edema (ME). METHODS: This was a retrospective cohort study of patients with ME secondary to retinal disease treated at ten Canadian retina practices, including one uveitis center. Best-corrected visual acuity (BCVA), central retinal thickness (CRT), intraocular pressure (IOP), glaucoma and cataract surgery, and safety data were collected from the medical charts of patients with ≥3 months of follow-up after the initial DEX implant. RESULTS: One hundred and one patient charts yielded data on 120 study eyes, including diagnoses of diabetic ME (DME) (n=34), retinal vein occlusion (RVO, n=30; branch in 19 and central in 11), and uveitis (n=23). Patients had a mean age of 60.9 years, and 73.3% of the study eyes had ME for a duration of ≥12 months prior to DEX implant injection(s). Baseline mean (± standard error) BCVA was 0.63±0.03 logMAR (20/86 Snellen equivalents) and mean CRT was 474.4±18.2 µm. The mean number of DEX implant injections was 1.7±0.1 in all study eyes; 44.2% of eyes had repeat DEX implant injections (reinjection interval 2.3-4.9 months). The greatest mean peak changes in BCVA lines of vision occurred in study eyes with uveitis (3.3±0.6, P<0.0001), followed by RVO (1.3±0.5, P<0.01) and DME (0.7±0.5, P>0.05). Significant decreases in CRT were observed: -255.6±43.6 µm for uveitis, -190.9±23.5 µm for DME, and -160.7±39.6 µm for RVO (P<0.0001 for all cohorts). IOP increases of ≥10 mmHg occurred in 20.6%, 24.1%, and 22.7% of DME, RVO, and uveitis study eyes, respectively. IOP-lowering medication was initiated in 29.4%, 16.7%, and 8.7% of DME, RVO, and uveitis study eyes, respectively. Glaucoma surgery was performed in 1.7% of all study eyes and cataract surgery in 29.8% of all phakic study eyes receiving DEX implant(s). CONCLUSION: DEX implant(s) alone or combined with other treatments and/or procedures resulted in functional and anatomic improvements in long-standing ME associated with retinal disease.

Prospective evaluation of teleophthalmology in screening and recurrence monitoring of neovascular age-related macular degeneration: a randomized clinical trial.

IMPORTANCE: Teleophthalmology has the potential to reduce costs and inconveniences associated with frequent patient visits. Evaluating teleophthalmology in the management of age-related macular degeneration (AMD) will allow for future implementation of this technology. OBJECTIVE: To evaluate teleophthalmology as a tool for the screening and monitoring of neovascular AMD. DESIGN, SETTING, AND PARTICIPANTS: Prospective, randomized clinical trial that included 106 referral eyes for suspected neovascular AMD and 63 eyes with stable neovascular AMD. New referrals for patients with suspected neovascular AMD and patients with stable neovascular AMD were randomized into either routine or teleophthalmologic groups. In the routine group, patients received clinical assessment and diagnostic imaging at a tertiary hospital-based retina clinic. In the teleophthalmologic group, patients received basic examination and diagnostic imaging at a stand-alone teleophthalmologic site, where patient information and imaging studies were acquired and electronically sent over to tertiary hospital-based retina specialists. Patients in the teleophthalmologic group were called back to the tertiary treatment center if the teleophthalmologic data set suggested pathology or was inconclusive for diagnosis. MAIN OUTCOMES AND MEASURES: Patient wait times for diagnosis and/or treatment, referral accuracy, and visual outcome. RESULTS: For neovascular AMD screening, the average referral-to-diagnostic imaging time was 22.5 days for the teleophthalmologic group and 18.0 days for the routine group, for a difference of 4.5 days (95% CI, 11.8 to -2.8 days; P = .23). The average diagnostic imaging to treatment time was 16.4 days for the teleophthalmologic group and 11.6 days for the routine group, for a difference of 4.8 days (95% CI, 10.7 to -1.1 days; P = .11). For neovascular AMD monitoring, the average recurrence to treatment time was shorter for the routine group (0.04 days) compared with 13.6 days for the teleophthalmologic group, for a difference of -13.5 days (95% CI, -18.2 to -9.0 days; P < .01). There was no difference identified between end-of-study visual acuities in the 2 groups (P = .99). CONCLUSIONS AND RELEVANCE: A delay of referral to treatment time could not be identified when comparing teleophthalmologic screening for suspected neovascular AMD with retinal specialist-based screening. Teleophthalmologic monitoring for neovascular AMD recurrence resulted in longer wait times for treatment reinitiation, but no adverse visual outcomes were identified. TRIAL REGISTRATION: clinicaltrials.gov Identifier:NCT01581606.

Severe visual loss secondary to retinal toxicity after intravenous use of bisphosphonate in an eye with known chloroquine maculopathy.

PURPOSE: To describe a case of retinal toxicity after intravenous administration of the bisphosphonate medication zoledronic acid. METHODS: A 61-year-old woman with known bull's eye chloroquine maculopathy presented with sudden decrease in vision within 1 week of receiving intravenous zoledronic acid (Aclasta). Complete ophthalmic examination including fundus photography, autofluorescence, optical coherence tomography, and visual field testing were performed over 1½ years of follow-up. RESULTS: Decreased visual acuity, central visual field depression, and loss of the outer retinal layers on optical coherence tomography were seen in the symptomatic eye. The patient's last dose of chloroquine was over 15 years ago, with stable visual acuity and visual fields over this period, making chloroquine maculopathy an unlikely cause for the acute visual decline. The temporal association with the administration of intravenous zoledronic acid suggests a causative role for this mediation. CONCLUSION: Exposure to zoledronic acid seems to have precipitated acute visual loss in an eye with known chloroquine toxicity after 15 years of quiescence. Retinal toxicity may represent a rare adverse reaction to zoledronic acid, but this case suggests that caution should be used when administering this medication to patients with compromised retinal integrity.

Intravitreal ranibizumab for the treatment of fibrovascular pigment epithelial detachment in age-related macular degeneration.

OBJECTIVE: To determine the response of predominantly fibrovascular pigment epithelial detachments (PED)-type lesions (secondary to age-related macular degeneration [AMD]) to intravitreal ranibizumab. DESIGN: This was an open-label prospective study. PARTICIPANTS: Thirty-two patients with predominantly fibrovascular PED-type lesions secondary to AMD were included in this study. Three patients were excluded from the final analysis. METHODS: Patients received monthly intravitreal ranibizumab injections for 6 months (induction). At 6 months, patients not experiencing a visual improvement from baseline Early Treatment of Diabetic Retinopathy Study (ETDRS) visual acuity or not showing a reduction in PED height (based on optical coherence tomography [OCT]) were deemed ranibizumab nonresponders and received no further injections but underwent re-evaluation at 12 months. Patients deemed responders continued with OCT-guided active treatment on an as-needed basis for an additional 6 months. RESULTS: Twenty-four patients (82.8%) were ranibizumab responders and 5 were (17.2%) nonresponders. For ranibizumab responders, mean ETDRS visual acuity improved by 7.2 ± 9.8 letters at 6 months (p = 0.002) and 6.3 ± 8.6 letters at 12 months (p = 0.002). Ranibizumab nonresponders experienced a decline in mean visual acuity of 8.2 ± 4.6 letters at 6 months (p = 0.02) and 18.2 ± 10.11 letters at 12 months (p = 0.02). At baseline, responders had a mean PED height of 345.8 ± 96.0 µm, which decreased to 111.6 ± 133.2 µm at 6 months (p < 0.001) and had a slight increase at 12 months to 144.8 ± 146.3 µm (p < 0.001). Two responders (8.3%) and 2 nonresponders (40%) developed retinal pigment epithelium tears while on treatment. CONCLUSIONS: Intravitreal ranibizumab appears to be a well-tolerated treatment option for patients with fibrovascular PED. Further large-scale, prospective studies may assist in delineating the best treatment protocol.

Canadian expert consensus: optimal treatment of neovascular age-related macular degeneration.

BACKGROUND: New therapeutic approaches, particularly anti-vascular endothelial growth factor (anti-VEGF) therapies, prevent, and in some cases reverse, vision damage caused by age-related macular degeneration (AMD). Unequal access to care across Canada remains a problem for many retina specialists and their patients. OBJECTIVE: To develop a consensus concerning the management of patients with exudative age-related macular degeneration (AMD). DESIGN: Consensus document. PARTICIPANTS: Ten Canadian retina specialists. METHODS: The development of a consensus among Canadian experts concerning optimal treatment of AMD began with a review of the clinical evidence, daily practices, existing guidelines, and current national and international approvals and policies. The experts met on June 29, 2010, in Quebec City to discuss their findings and to propose strategies for consensus. RESULTS: The result of this expert panel is a consensus proposal for Canadian ophthalmologists and retina specialists who are treating patients with or at risk for developing neovascular AMD. CONCLUSIONS: The consensus provides guidelines to aid retina specialists in managing exudative AMD. Currently, ranibizumab is the only agent with sufficient Level I evidence and a Health Canada-approved indication for the treatment of wet AMD. Bevacizumab has been shown to be noninferior in preserving and improving visual acuity when compared to ranibizumab. Potential safety differences between the 2 drugs remain to be elucidated. The positioning of ranibizumab in this therapeutic area will be further defined as additional data for existing and emerging therapies become available. Until then, this agent remains the therapy of choice for individuals with neovascular AMD.

Severe retinopathy of prematurity associated with FZD4 mutations.

PURPOSE: To determine whether mutations in the FZD4 gene are a risk factor for developing severe ROP. METHODS: Three Canadian tertiary care centers recruited premature infants prospectively and retrospectively, and assigned affectation status based on the maximum degree of severity of ROP recorded in both eyes. Mutation screening of the FZD4 gene was performed using direct sequencing. All sequence changes were evaluated for functional significance. RESULTS: Two novel FZD4 mutations (Ala370Gly or Lys203Asn) were identified in two infants from the severe ROP group (n=71). No mutation was detected in the mild to no ROP group (n=33), and the two novel mutations were absent in 173 random Caucasian samples. Mutation Ala370Gly was also found in one sibling and one parent of the affected infant, but no signs of familial exudative vitreoretinopathy (FEVR), a condition with phenotypic overlap with ROP known to be caused by FZD4 mutations, were present in either family member. CONCLUSIONS: Mutations in the FZD4 gene in this group of premature infants supports a role for the FZD4 pathway in the development of severe ROP and accounts for approximately 3% of severe ROP in Caucasian premature infants.

Verteporfin photodynamic therapy combined with intravitreal bevacizumab for neovascular age-related macular degeneration.

PURPOSE: To assess outcomes for patients with choroidal neovascularization (CNV) due to age-related macular degeneration (AMD) treated with verteporfin photodynamic therapy (PDT) and bevacizumab. DESIGN: Retrospective, case series database study (registry). PARTICIPANTS: We included 1196 patients with CNV due to AMD who received > or =1 combination treatment of 1.25 mg intravitreal bevacizumab within 14 days of verteporfin PDT. METHODS: Retrospective analysis of baseline data with ongoing follow-up. Physicians from 45 clinical centers entered patient data at baseline and follow-up examinations, including subsequent treatments, into a secure, Web-accessed database. Snellen visual acuity (VA) was converted to logarithm of the minimum angle of resolution (logMAR) for statistical analyses. MAIN OUTCOME MEASURES: Change from baseline in VA and retreatment rates of any therapy after the initial combination treatment. RESULTS: Of 1196 patients, 1073 patients had > or =6 months of follow-up. For these 1073 patients, mean baseline VA was 0.967 logMAR (approximate Snellen 20/185) and 56.3% of patients (604/1073) were treatment naïve. After their baseline combination treatment, patients received a mean of 0.6 additional verteporfin PDT retreatments and 2.0 bevacizumab retreatments over a mean follow-up period of 15.0 months. By 12 months, 82% of patients (578/701) had stable or improved vision (loss of <3 lines or a gain in VA), 36% (255/701) improved by > or =3 lines, and 17% (121/701) improved by > or =6 lines. By 12 months, patients gained approximately 1.2 lines (6 letters) of VA from baseline. Patients who were treatment naïve gained significantly more VA by month 12 (+8.4 letters) compared with those who had been previously treated (+2.4 letters; P<0.01). Most serious adverse events (26/30) were judged by investigators as not related to any study treatment, although 3 ocular events were judged related to bevacizumab alone, and 1 ocular event was judged related to both bevacizumab and PDT. CONCLUSIONS: Combination therapy with PDT and bevacizumab led to vision benefit for most patients, particularly those who were treatment naïve at baseline. The number of retreatments was lower than published reports with either treatment delivered as monotherapy. Randomized clinical trials are underway to confirm these findings.

Prospective evaluation of digital non-stereo color fundus photography as a screening tool in age-related macular degeneration.

PURPOSE: To evaluate mydriatic, non-stereo digital color fundus photographs as a screening tool for identifying and classifying exudative age-related macular degeneration (AMD). DESIGN: Prospective case series. METHODS: Digital color fundus photographs were obtained from patients seen in the AMD screening clinic over a 9-month period at the Ivey Eye Institute in London, Ontario. Photographs for eligible patients were separated by eye, cataloged, blinded, and randomly labeled before interpretation by an experienced vitreoretinal surgeon. Exact agreement, sensitivity, specificity, positive predictive value, and negative predictive value of the fundus photographs in diagnosing, classifying, and managing cases of suspected exudative AMD were then calculated against gold standard clinical examination and fluorescein angiography. RESULTS: A total of 223 images were used from 118 eligible patients. Exact agreement between photographic evaluation and gold standard ranged from 89.2% (presence of pigment epithelial detachment (PED)) to 82.5% (evidence of retinal pigment epithelium geographic atrophy). Sensitivities ranged from 89.2% (presence of choroidal neovascular membrane (CNVM)) to 40.0% (presence of PED). Specificities ranged from 94.1% (presence of PED) to 86.8% (presence of retinal pigment epithelium geographic atrophy). Positive predictive value ranged from 86.1% (presence of CNVM) to 40.0% (presence of PED). Negative predictive value ranged from 94.1% (presence of PED) to 88.9% (presence of CNVM). As a screening tool for high-risk dry changes and active exudative changes, overall sensitivity specificity, positive predictive value, and negative predictive value were 82.1%, 79.1%, 70.4%, and 88.0%, respectively. CONCLUSIONS: Digital, non-stereo color fundus photographs are highly sensitive and have high negative predictive value as a screening tool. Very few treatable lesions are missed using telemedicine in age-related macular degeneration.

Outcome of macular hole surgery in diabetic patients with nonproliferative retinopathy.

PURPOSE: To determine the outcome of macular hole surgery in a diabetic population with no evidence of proliferative retinopathy. METHODS: This is a retrospective chart review of 183 patients (194 eyes) undergoing pars plana vitrectomy for an idiopathic macular hole. RESULTS: The anatomic closure rate for the diabetic patients without proliferative retinopathy was 93.8% (15/16), compared with 94.9% (169/178) for nondiabetic patients. A best corrected visual acuity of 20/50 or greater was obtained in 50% of diabetic patients (8/16), compared to 58.4% of nondiabetic patients (104/178). There was no difference in postoperative complications between the two groups. CONCLUSION: The anatomic closure rate and visual outcome after macular hole surgery in diabetic patients without proliferative retinopathy is comparable to that of nondiabetic patients.

Central serous chorioretinopathy in a patient taking sildenafil citrate.

A 37-year-old man presented with decreased vision in the right eye following increased use of sildenafil citrate. The visual and clinical findings worsened during the following week with continued use and then resolved rapidly with discontinuation of sildenafil citrate.