Timothy Y. Y. Lai

Revised Recommendations on Screening for Chloroquine and Hydroxychloroquine Retinopathy

BACKGROUND The American Academy of Ophthalmology recommendations for screening of chloroquine (CQ) and hydroxychloroquine (HCQ) retinopathy were published in 2002, but improved screening tools and new knowledge about the prevalence of toxicity have appeared in the ensuing years. No treatment exists as yet for this disorder, so it is imperative that patients and their physicians be aware of the best practices for minimizing toxic damage. RISK OF TOXICITY New data have shown that the risk of toxicity increases sharply toward 1% after 5 to 7 years of use, or a cumulative dose of 1000 g, of HCQ. The risk increases further with continued use of the drug. DOSAGE The prior recommendation emphasized dosing by weight. However, most patients are routinely given 400 mg of HCQ daily (or 250 mg CQ). This dose is now considered acceptable, except for individuals of short stature, for whom the dose should be determined on the basis of ideal body weight to avoid overdosage. SCREENING SCHEDULE A baseline examination is advised for patients starting these drugs to serve as a reference point and to rule out maculopathy, which might be a contraindication to their use. Annual screening should begin after 5 years (or sooner if there are unusual risk factors). SCREENING TESTS Newer objective tests, such as multifocal electroretinogram (mfERG), spectral domain optical coherence tomography (SD-OCT), and fundus autofluorescence (FAF), can be more sensitive than visual fields. It is now recommended that along with 10-2 automated fields, at least one of these procedures be used for routine screening where available. When fields are performed independently, even the most subtle 10-2 field changes should be taken seriously and are an indication for evaluation by objective testing. Because mfERG testing is an objective test that evaluates function, it may be used in place of visual fields. Amsler grid testing is no longer recommended. Fundus examinations are advised for documentation, but visible bulls-eye maculopathy is a late change, and the goal of screening is to recognize toxicity at an earlier stage. COUNSELING Patients should be aware of the risk of toxicity and the rationale for screening (to detect early changes and minimize visual loss, not necessarily to prevent it). The drugs should be stopped if possible when toxicity is recognized or strongly suspected, but this is a decision to be made in conjunction with patients and their medical physicians.

EVEREST study: efficacy and safety of verteporfin photodynamic therapy in combination with ranibizumab or alone versus ranibizumab monotherapy in patients with symptomatic macular polypoidal choroidal vasculopathy.

Purpose: To assess the effects of verteporfin photodynamic therapy (PDT) combined with ranibizumab or alone versus ranibizumab monotherapy in patients with symptomatic macular polypoidal choroidal vasculopathy. Methods: In this multicenter, double-masked, primarily indocyanine green angiography–guided trial, 61 Asian patients were randomized to verteporfin PDT (standard fluence), ranibizumab 0.5 mg, or the combination. Patients were administered with verteporfin PDT/placebo and initiated with three consecutive monthly ranibizumab/sham injections starting Day 1, and re-treated (Months 3–5) as per predefined criteria. The primary endpoint was the proportion of patients with indocyanine green angiography–assessed complete regression of polyps at Month 6. Secondary endpoints included mean change in best-corrected visual acuity at Month 6 and safety. Results: At Month 6, verteporfin combined with ranibizumab or alone was superior to ranibizumab monotherapy in achieving complete polyp regression (77.8% and 71.4% vs. 28.6%; P < 0.01); mean change ± standard deviation in best-corrected visual acuity (letters) was 10.9 ± 10.9 (verteporfin PDT + ranibizumab), 7.5 ± 10.6 (verteporfin PDT), and 9.2 ± 12.4 (ranibizumab). There were no new safety findings with either drug used alone or in combination. Conclusion: Verteporfin PDT combined with ranibizumab 0.5 mg or alone was superior to ranibizumab monotherapy in achieving complete regression of polyps in this 6-month study in patients with symptomatic macular polypoidal choroidal vasculopathy. All treatments were well tolerated over 6 months.

Safety enhanced photodynamic therapy for chronic central serous chorioretinopathy: one-year results of a prospective study.

Purpose: To evaluate the efficacy of a safety enhanced photodynamic therapy (PDT) protocol with half-dose verteporfin for treating chronic central serous chorioretinopathy (CSC). Methods: Forty-eight eyes of 48 patients with symptomatic chronic CSC underwent indocyanine green angiography guided PDT with half dose (3 mg/m2) verteporfin. Outcome measures included logMAR best-corrected visual acuity (BCVA), central retinal thickness, and angiographic changes during the 12-month study period. Results: The mean CSC duration was 8.2 months (range, 3–40 months). At 12 months after PDT, the mean logMAR BCVA improved from 0.31 to 0.15 (P < 0.001). The mean improvement was 1.6 lines and 45 (95.8%) eyes had stable or improved vision. Eyes without pigment epithelial detachment (PED) had significantly greater visual improvement compared with eyes with PED (P = 0.031). Patients with CSC of 6 months or less or younger than 45 years were more likely to gain vision by two or more lines after treatment (P = 0.007 and P = 0.018, respectively). Forty (83.3%) eyes had complete resolution of serous detachment at 3 months, with 43 (89.6%) eyes at 12 months. Conclusions: The safety enhanced PDT protocol appeared to be beneficial for patients with chronic CSC. Further controlled study is warranted to evaluate the safety and efficacy of this treatment option.

Safety enhanced photodynamic therapy with half dose verteporfin for chronic central serous chorioretinopathy: a short term pilot study.

Aim: To evaluate short term safety of an enhanced photodynamic therapy (PDT) protocol with half dose verteporfin for treating chronic central serous chorioretinopathy (CSC). Methods: 20 eyes of 18 patients with symptomatic chronic CSC underwent PDT using 3 mg/m2 verteporfin. Verteporfin was infused over 8 minutes followed by indocyanine green angiography guided laser application 2 minutes later. Serial optical coherence tomography (OCT) and multifocal electroretinography (mfERG) recordings were performed before PDT, at 4 days, 2 weeks, and 1 month after PDT. The best corrected visual acuity (BCVA), OCT central retinal thickness, and mean mfERG response amplitudes and peak latencies were compared longitudinally. Subgroup analysis was further performed for eyes with or without pigment epithelial detachment (PED). Results: At 1 month after PDT, the median BCVA improved from 20/40 to 20/30 (p = 0.001). The mean central retinal thickness also reduced from 276 μm to 158 μm (p<0.001) and 17 (85%) eyes had complete resolution of serous retinal detachment and/or PED. MfERG showed no significant changes in the mean N1 and P1 response amplitude and latency for all eyes. Subgroup analysis demonstrated that eyes without PED had a significant increase in the mean central mfERG P1 response amplitude with reduction in P1 peak latency at 1 month post-PDT. For eyes with PED, transient reduction in the mean central P1 response amplitude was observed at 4 days post-PDT. Conclusions: The modified safety enhanced PDT protocol with half dose verteporfin appeared to be a beneficial treatment option for patients with chronic CSC, especially in eyes without serous PED. Further controlled study is warranted to demonstrate the long term safety and efficacy of this treatment option.

Polypoidal choroidal vasculopathy: evidence-based guidelines for clinical diagnosis and treatment.

Background: Polypoidal choroidal vasculopathy (PCV) is an exudative maculopathy affecting vision, with clinical features distinct from neovascular age-related macular degeneration. Currently, no evidence-based guidelines exist for its diagnosis and treatment. Methods: A panel of experts analyzed a systematic literature search on PCV together with results of the EVEREST trial, the only published randomized controlled clinical trial in PCV. At a subsequent Roundtable meeting, recommendations for the management of PCV were agreed based on this analysis and their own expert opinion. Results: Diagnosis of PCV should be based on early-phase nodular hyperfluorescence from choroidal vasculature visualized using indocyanine green angiography. Recommended initial treatment of juxtafoveal and subfoveal PCV is either indocyanine green angiography-guided verteporfin photodynamic therapy or verteporfin photodynamic therapy plus 3 × 0.5 mg ranibizumab intravitreal injections 1 month apart. If there is incomplete regression of polyps by indocyanine green angiography, eyes should be retreated with verteporfin photodynamic therapy monotherapy or verteporfin photodynamic therapy plus ranibizumab. If there is complete regression of polyps by indocyanine green angiography, but there is leakage on fluorescein angiography and other clinical or anatomical signs of disease activity, eyes should be retreated with ranibizumab. Conclusion: Practical guidance on the clinical management of PCV is proposed based on expert evaluation of current evidence.

Intravitreal bevacizumab (Avastin) with or without photodynamic therapy for the treatment of polypoidal choroidal vasculopathy

Aim: To evaluate the efficacy of intravitreal bevacizumab (Avastin) with or without verteporfin photodynamic therapy (PDT) in the treatment of polypoidal choroidal vasculopathy (PCV). Methods: Fifteen eyes of 15 patients with symptomatic PCV who received three monthly intravitreal bevacizumab were retrospectively reviewed. Subsequent retreatments with intravitreal bevacizumab and/or PDT were performed in patients with recurrent or persistent polypoidal lesions on indocyanine green angiography (ICGA), and persistent or recurrent subretinal fluid. Results: The mean follow-up duration was 12.8 months. At 3 months, the mean logMAR BCVA improved from 0.61 to 0.51 (p = 0.014), and the mean CFT reduced from 347 μm to 247 μm (p = 0.015). Despite the visual and anatomical improvements, persistent polyps were present in ICGA of all eyes at 3 months. At the last follow-up, mean BCVA remained at 0.51 after additional treatment with intravitreal bevacizumab and/or PDT (p = 0.022). Patients who had subsequent PDT were less likely to have persistent polypoidal lesions on ICGA at the last visit (p = 0.041). Conclusions: Intravitreal bevacizumab appeared to result in stabilisation of vision and reduction of exudative retinal detachment in PCV patients. However, intravitreal bevacizumab monotherapy had limited effectiveness in causing regression of the polypoidal lesions in ICGA, and additional PDT appeared to be useful for treating these lesions.

Recommendations on Screening for Chloroquine and Hydroxychloroquine Retinopathy (2016 Revision)

BACKGROUND The American Academy of Ophthalmology recommendations on screening for chloroquine (CQ) and hydroxychloroquine (HCQ) retinopathy are revised in light of new information about the prevalence of toxicity, risk factors, fundus distribution, and effectiveness of screening tools. PATTERN OF RETINOPATHY Although the locus of toxic damage is parafoveal in many eyes, Asian patients often show an extramacular pattern of damage. DOSE: We recommend a maximum daily HCQ use of ≤5.0 mg/kg real weight, which correlates better with risk than ideal weight. There are no similar demographic data for CQ, but dose comparisons in older literature suggest using ≤2.3 mg/kg real weight. RISK OF TOXICITY The risk of toxicity is dependent on daily dose and duration of use. At recommended doses, the risk of toxicity up to 5 years is under 1% and up to 10 years is under 2%, but it rises to almost 20% after 20 years. However, even after 20 years, a patient without toxicity has only a 4% risk of converting in the subsequent year. MAJOR RISK FACTORS High dose and long duration of use are the most significant risks. Other major factors are concomitant renal disease, or use of tamoxifen. SCREENING SCHEDULE A baseline fundus examination should be performed to rule out preexisting maculopathy. Begin annual screening after 5 years for patients on acceptable doses and without major risk factors. SCREENING TESTS The primary screening tests are automated visual fields plus spectral-domain optical coherence tomography (SD OCT). These should look beyond the central macula in Asian patients. The multifocal electroretinogram (mfERG) can provide objective corroboration for visual fields, and fundus autofluorescence (FAF) can show damage topographically. Modern screening should detect retinopathy before it is visible in the fundus. TOXICITY Retinopathy is not reversible, and there is no present therapy. Recognition at an early stage (before any RPE loss) is important to prevent central visual loss. However, questionable test results should be repeated or validated with additional procedures to avoid unnecessary cessation of valuable medication. COUNSELING Patients (and prescribing physicians) should be informed about risk of toxicity, proper dose levels, and the importance of regular annual screening.

Choroidal neovascularization in pathological myopia

Myopic choroidal neovascularization (CNV) is one of the leading causes of visual impairment worldwide. The clinical and socioeconomic impact of myopic CNV in Asian countries is particularly significant due to rising trend in the prevalence and severity of pathological myopia. The exact pathogenesis of myopic CNV remains unclear and there is paucity of information with respect to incidence and risk factors for myopic CNV from prospective studies. Furthermore, there are no recognized measures that may prevent or delay the development of CNV in eyes with pathological myopia. Advances have been made in the diagnosis and characterization of myopic CNV over the years. Until recently, treatment modalities for myopic CNV were limited to thermal laser photocoagulation and photodynamic therapy with verteporfin, both these modalities primarily aim at prevention of further visual loss. In the last 5 years, inhibitors of vascular endothelial growth factor (VEGF) have been used successfully and may improve vision to some extent. Nevertheless, the long-term safety and efficacy of anti-VEGF agents remains unknown. Furthermore, the risk of developing chorioretinal atrophy remains the key factor in determining the final visual outcome. This review article summarizes the current literature on myopic CNV, highlighting new evolving diagnostic and treatment modalities, prognostic factors influencing visual outcome, and areas of future research.

Indocyanine green assisted retinal internal limiting membrane removal in stage 3 or 4 macular hole surgery

Aims: To determine surgical outcome in primary idiopathic stage 3 or 4 macular holes with indocyanine green (ICG) assisted retinal internal limiting membrane (ILM) peeling. Methods: A prospective, consecutive, interventional case series with 41 eyes of 40 patients was included. No patient defaulted follow up. Besides a standard macular hole surgery, all eyes received ICG assisted ILM removal of 3–4 disc diameters around macular holes. At the end of the surgery, 12% perfluoropropane gas was used. A face down posture for 2 weeks was required postoperatively. Results: The mean follow up period was 15.1 months (range 6–24 months). Twenty (48.8%) eyes had stage 3 macular holes and 21 (51.2%) had stage 4 macular holes. The overall median duration of holes was 11 months. 19 (46.3%) were chronic macular holes of more than 12 months’ duration. The anatomical success rates after one surgery was 87.8% (36 eyes), while that of chronic and non-chronic ones was 78.9% and 95.5%, respectively. The median preoperative and postoperative visual acuity was 20/200 (range 20/60 to counting fingers) and 20/100 (range 20/20 to 20/400), respectively. 24 (58.5%) eyes had improvement of two or more Snellen lines. The mean was 3.2 lines (range two to nine lines), with 3.6 lines and 2.7 lines for non-chronic and chronic holes, respectively. For all the 41 eyes, 16 (39%) eyes had a final visual acuity of 20/50 or better. Conclusion: ICG assisted retinal ILM removal, in idiopathic primary chronic and non-chronic stage 3 or 4 macular hole surgery, appears to give a promising anatomical closure rate without compromising the visual result.

Intravitreal bevacizumab (Avastin) for myopic choroidal neovascularisation: 1-year results of a prospective pilot study.

Aim: The aim of the study was to examine the 1-year results of intravitreal bevacizumab for myopic choroidal neovascularisation (CNV). Methods: Twenty-nine eyes of 29 patients with myopic CNV were prospectively recruited to receive three initial monthly intravitreal bevacizumab injections. Three additional monthly injections were performed in eyes with persistent or recurrent CNV after 3 months. Results: The mean spherical equivalent refractive error was −10.0 D. Sixteen eyes had previous photodynamic therapy (PDT) and 13 eyes had no prior PDT. All patients completed follow-up at 1 year. Following the initial three bevacizumab injections, 27 (93.1%) eyes had angiographic closure and two (6.9%) required further treatment. Two additional patients required re-treatment for CNV recurrence between 6 and 9 months. The mean baseline logarithm of the minimum angle of resolution (logMAR best-corrected visual acuity) was 0.62 (20/83), which improved to 0.38 (20/48) at 12 months (p<0.001). The mean visual improvement was 2.4 lines and 21 (72.4%) eyes had improvement of ⩾2 lines. Optical coherence tomography showed significant reduction in central foveal thickness following treatment. Eyes without previous PDT were more likely to gain ⩾2 lines after treatment than eyes that had previous PDT (p = 0.010). Conclusions: The 1-year outcomes confirmed the results of previous short-term studies that intravitreal bevacizumab is effective for myopic CNV, with a high proportion of patients sustaining visual gain after treatment.