Sajjad Mahmood

Defining response to anti-VEGF therapies in neovascular AMD

The introduction of anti-vascular endothelial growth factor (anti-VEGF) has made significant impact on the reduction of the visual loss due to neovascular age-related macular degeneration (n-AMD). There are significant inter-individual differences in response to an anti-VEGF agent, made more complex by the availability of multiple anti-VEGF agents with different molecular configurations. The response to anti-VEGF therapy have been found to be dependent on a variety of factors including patient’s age, lesion characteristics, lesion duration, baseline visual acuity (VA) and the presence of particular genotype risk alleles. Furthermore, a proportion of eyes with n-AMD show a decline in acuity or morphology, despite therapy or require very frequent re-treatment. There is currently no consensus as to how to classify optimal response, or lack of it, with these therapies. There is, in particular, confusion over terms such as ‘responder status’ after treatment for n-AMD, ‘tachyphylaxis’ and ‘recalcitrant’ n-AMD. This document aims to provide a consensus on definition/categorisation of the response of n-AMD to anti-VEGF therapies and on the time points at which response to treatment should be determined. Primary response is best determined at 1 month following the last initiation dose, while maintained treatment (secondary) response is determined any time after the 4th visit. In a particular eye, secondary responses do not mirror and cannot be predicted from that in the primary phase. Morphological and functional responses to anti-VEGF treatments, do not necessarily correlate, and may be dissociated in an individual eye. Furthermore, there is a ceiling effect that can negate the currently used functional metrics such as >5 letters improvement when the baseline VA is good (ETDRS>70 letters). It is therefore important to use a combination of both the parameters in determining the response.The following are proposed definitions: optimal (good) response is defined as when there is resolution of fluid (intraretinal fluid; IRF, subretinal fluid; SRF and retinal thickening), and/or improvement of >5 letters, subject to the ceiling effect of good starting VA. Poor response is defined as <25% reduction from the baseline in the central retinal thickness (CRT), with persistent or new IRF, SRF or minimal or change in VA (that is, change in VA of 0+4 letters). Non-response is defined as an increase in fluid (IRF, SRF and CRT), or increasing haemorrhage compared with the baseline and/or loss of >5 letters compared with the baseline or best corrected vision subsequently. Poor or non-response to anti-VEGF may be due to clinical factors including suboptimal dosing than that required by a particular patient, increased dosing intervals, treatment initiation when disease is already at an advanced or chronic stage), cellular mechanisms, lesion type, genetic variation and potential tachyphylaxis); non-clinical factors including poor access to clinics or delayed appointments may also result in poor treatment outcomes. In eyes classified as good responders, treatment should be continued with the same agent when disease activity is present or reactivation occurs following temporary dose holding. In eyes that show partial response, treatment may be continued, although re-evaluation with further imaging may be required to exclude confounding factors. Where there is persistent, unchanging accumulated fluid following three consecutive injections at monthly intervals, treatment may be withheld temporarily, but recommenced with the same or alternative anti-VEGF if the fluid subsequently increases (lesion considered active). Poor or non-response to anti-VEGF treatments requires re-evaluation of diagnosis and if necessary switch to alternative therapies including other anti-VEGF agents and/or with photodynamic therapy (PDT). Idiopathic polypoidal choroidopathy may require treatment with PDT monotherapy or combination with anti-VEGF. A committee comprised of retinal specialists with experience of managing patients with n-AMD similar to that which developed the Royal College of Ophthalmologists Guidelines to Ranibizumab was assembled. Individual aspects of the guidelines were proposed by the committee lead (WMA) based on relevant reference to published evidence base following a search of Medline and circulated to all committee members for discussion before approval or modification. Each draft was modified according to feedback from committee members until unanimous approval was obtained in the final draft. A system for categorising the range of responsiveness of n-AMD lesions to anti-VEGF therapy is proposed. The proposal is based primarily on morphological criteria but functional criteria have been included. Recommendations have been made on when to consider discontinuation of therapy either because of success or futility. These guidelines should help clinical decision-making and may prevent over and/or undertreatment with anti-VEGF therapy.

Ranibizumab 0.5 mg treat-and-extend regimen for diabetic macular oedema: the RETAIN study

Aims To demonstrate non-inferiority of ranibizumab treat-and-extend (T&E) with/without laser to ranibizumab pro re nata (PRN) for best-corrected visual acuity (BCVA) in patients with diabetic macular oedema (DMO). Methods A 24-month single-masked study with patients randomised 1:1:1 to T&E+laser (n=121), T&E (n=128) or PRN (control; n=123). All patients received monthly injections until BCVA stabilisation. The investigator decided on re-treatment in the PRN and treatment-interval adaptations in the T&E groups based on loss of BCVA stability due to DMO activity. Likewise, laser treatment was at investigators discretion. Collectively, these features reflect a real-life scenario. Endpoints included mean average change in BCVA from baseline to months 1–12 (primary), mean BCVA change from baseline to months 12 and 24, treatment exposure and safety profile. Results Both T&E regimens were non-inferior to PRN based on mean average BCVA change from baseline to months 1–12 (T&E+laser: +5.9 and T&E: +6.1 vs PRN: +6.2 letters; both p<0.0001). Mean BCVA change at month 24 was similar across groups (+8.3, +6.5 and +8.1 letters, respectively). The mean number of injections was 12.4 and 12.8 in the T&E+laser and T&E groups and 10.7 in the PRN group. The T&E regimens showed 46% reduction in the number of clinic visits. Over 70% of patients maintained their BCVA, with treatment intervals of ≥2 months over 24 months. Safety profile was consistent with that described in the product information. Conclusions T&E is a feasible treatment option for patients with DMO, with a potential to reduce treatment burden. Slightly more injections were required versus PRN, likely due to the specifics of the T&E regimen applied here. Trial registration number NCT01171976.

Displacement of nuclear fragments into the vitreous complicating phacoemulsification surgery in the UK: incidence and risk factors

Aims: To study the epidemiology and risk factors contributing to displacement of nuclear fragments into the vitreous (DNFV) complicating phacoemulsification in the UK. Methods: Cases were collected prospectively between March 2003 and March 2004 by active surveillance through the British Ophthalmological Surveillance Unit (BOSU). Case–control analysis of risk factors was performed by visiting 10 randomly selected centres using a total of 521 cases of uncomplicated phacoemulsification. Validation analysis to assess under-reporting was performed in a total of 13 randomly selected units. Results: 610 cases of DNFV were confirmed during the reporting period. The estimated incidence of DNFV was 0.19–0.28%. The group with complications was significantly older than the control group (mean 76.8 vs 74.3 years: p<0.001). Significant preoperative risk factors were posterior synechiae (5.1% vs 2.2%), incomplete pupil dilation (59.5% vs 8.8%), pseudoexfoliation (5.6% vs 1.4%) and previous vitrectomy (7.8% vs 2.2%). Significant operative variables related to surgical experience, topical (14.3% vs 3.1%) and sub-Tenon’s (51.4% vs 37.2%) anaesthesia, and requirement for vision blue (trypan blue ophthalmic solution) (13.7% vs 2.4%). Conclusions: The estimated incidence of DNFV during phacoemulsification surgery in the UK is two or three per 1000 operations. Risk factors have been identified that should help to guide case selection for phacoemulsification surgery and modify techniques.

Displacement of nuclear fragments into the vitreous complicating phacoemulsification surgery in the UK: clinical features, outcomes and management

Aims: To study the clinical features, management and outcomes of displacement of nuclear fragments into the vitreous (DNFV) complicating phacoemulsification in the UK. Methods: Cases were collected prospectively between March 2003 and March 2004 inclusive by active surveillance through the British Ophthalmological Surveillance Unit. Details were obtained using incidence questionnaires and follow-up questionnaires after 6 months. The data used in this paper were obtained from the follow-up questionnaires. Results: 610 cases were confirmed during the reporting period, for which 387 follow-up questionnaires were received. In 67% of cases, a best-corrected visual acuity of 6/12 or better was reported at final follow-up. The most common immediate sequelae of DNFV were intraocular inflammation (85%), corneal oedema (55%) and an intraocular pressure >30 mm Hg (34%). Pars plana vitreolensectomy was used in 97% of cases, and fragmatome ultrasound lensectomy was used in over half of these procedures. The median time from cataract surgery to pars plana vitrectomy for the removal of DNFV was 3 days, and most patients (68%) had vitrectomy within 1 week of the first procedure. An intraocular lens had been inserted at the time of the complicated cataract surgery (defined as a “primary IOL”) in 40% of cases, and over three-quarters of these primary IOLs were subsequently removed (with or without a replacement IOL). Only 67% of eyes that had a primary IOL inserted after DNFV were pseudophakic at final follow-up, in contrast with 79% of eyes that were left aphakic after DNFV (p = 0.008). A best-corrected visual acuity of 6/60 or worse was reported in 14% of cases at final follow-up and was most commonly associated with persistent uveitis, corneal oedema, cystoid macular oedema, optic atrophy or retinal detachment. Conclusions: DNFV complicating cataract surgery was followed by a secondary procedure in 97% of cases. About three-quarters (77%) of “primary IOLs” inserted at the time of DNFV were subsequently removed or replaced, and eyes that had received a primary IOL had significantly less chance of being pseudophakic at final follow-up than eyes that had been left primarily aphakic at the time of the complicated cataract surgery. The delay before secondary intervention was shorter, fragmatome ultrasound lensectomy use was higher, and the retinal detachment rate was lower than in previous studies. Affected eyes still had a worse outcome in terms of visual acuity compared with eyes after uncomplicated cataract surgery.

Early response of retinal angiomatous proliferation treated with intravitreal pegaptanib : a retrospective review

Aims To evaluate the early functional and anatomical responses to intravitreal pegaptanib in patients with retinal angiomatous proliferation (RAP).Methods Retrospective review of consecutive patients newly diagnosed with RAP treated with intravitreal pegaptanib (0.3 mg). Examination at baseline and 12 weekly intervals included refraction protocol best corrected visual acuity (BCVA), fluorescein angiography (FA), and optical coherence tomography (OCT). At intervening 6 weekly visits a reduced protocol assessment included BCVA and OCT.Results A total of 16 eyes of 16 patients (12 female, mean age 76.0 years) with RAP at baseline (15 stage 3, one stage 2) were treated. One patient had poor response, losing 20 ETDRS letters after one injection and was switched to photodynamic therapy combined with intravitreal triamcinolone. Mean BCVA (n=15) was baseline 45±11 (mean±SD) letters, 12 weeks 43±14 letters, 24 weeks 40±14 letters; the reduction from baseline to 24 weeks was statistically significant (P=0.04). Vision remained stable defined as ±15 letters of baseline BCVA in 13 (87%) of patients 2 (13%) lost >15 letters. Mean OCT central foveal thickness (CFT) (n=13) was: baseline 325±123 μm, 12 weeks 343±130 μm, 24 weeks 321±115 μm; difference at 24 weeks was not statistically significant (P=0.9). A pigment epithelial detachment was present in 12 cases; height was reduced in 10 cases at 24 weeks. Persistent leakage on FA was seen in 13 out of 15 cases at 24 weeks.Conclusion Early results of treatment of RAP with intravitreal pegaptanib suggest some stabilizing effect on this normally progressive disease.

Aflibercept in wet AMD beyond the first year of treatment: recommendations by an expert roundtable panel

This supplement has been sponsored by Bayer HealthCare. Please see acknowledgements for full disclaimer. Prescribing Information can be found in the appendices. L.GB.COM.05.2015.11280. Date of preparation: June 2015 This paper provides expert recommendations on administration of aflibercept in wet age-related macular degeneration (AMD) after Year 1 (Y1), based on a roundtable discussion held in London, UK in November 2014. The goals of treatment after Y1 are to maintain visual and anatomical gains whilst minimising treatment burden and using resources effectively. The treatment decision should be made at the seventh injection visit (assuming the label has been followed) in Y1, and three approaches are proposed: (a) eyes with active disease on imaging/examination but with stable visual acuity (VA) at the end of Y1 should continue with fixed 8-weekly dosing; (b) eyes with inactive disease on imaging/examination and stable VA should be managed using a ‘treat and extend’ (T&E) regimen. T&E involves treating and then extending the interval until the next treatment, by 2-week intervals, to a maximum of 12 weeks, provided the disease remains inactive. If there is new evidence of disease activity, treatment is administered and the interval to the next treatment shortened; and (c) if there has been no disease activity for ≥3 consecutive visits, a trial of monitoring without treatment may be appropriate, initiated at the end of Y1 or at any time during Y2. Where possible, VA testing, OCT imaging and injection should be performed at the same visit. The second eye should be monitored to detect fellow eye involvement. In bilateral disease, the re-treatment interval should be driven by the better-seeing eye or, if the VA is similar, the eye with the more active disease.

Erratum: Defining response to anti-VEGF therapies in neovascular AMD

Correction to: Eye (2015) 29, 721–731; doi:10.1038/eye.2015.48; published online 17 April 2015 Since the online publication of the above article, the authors have noted that the name of the ninth author was published incorrectly. The correct name is SP Kelly. The authors have also noted that the conflict of interest statements were not complete.

Ranibizumab for the management of Sorsby fundus dystrophy

Sir, Sorsby fundus dystrophy is a rare retinal dystrophy of autosomal-dominant inheritance characterized by central vision loss before the fifth decade of life, secondary to choroidal neovascularization (CNV) and/or pigment epithelium atrophy. The natural history of the condition involves early development of lesion fibrosis.1 The genetic background of the disease resides in a mutation in the tissue inhibitor of metalloproteinase 3 (TIMP3) gene.2 We report here a case of Sorsby fundus dystrophy successfully treated with repeated injections of ranibizumab.

Solar retinopathy in a patient with bipolar affective disorder

The commonest cause of solar retinopathy is direct viewing of a solar eclipse.1 Other associations include sun gazing during religious rituals, drug or alcohol intoxication, and mental illness.2,,3 However, it may not be considered in the absence of a history of sun gazing. We report an unusual case of solar retinopathy in a patient with bipolar affective disorder and demonstrate the value of optical coherence tomography in aiding the diagnosis in cases of unexplained visual loss in patients with mental illness. A 45 year old woman presented complaining of a gradual deterioration in vision over 3 years. Past medical history included hypothyroidism and bipolar affective disorder treated with antidepressant and antipsychotic medication. Presenting visual acuities were 6/12 in the right eye and 6/9 …

The United Kingdom Diabetic Retinopathy Electronic Medical Record Users Group, Report 1: baseline characteristics and visual acuity outcomes in eyes treated with intravitreal injections of ranibizumab for diabetic macular oedema

Aims To describe baseline characteristics and visual outcome for eyes treated with ranibizumab for diabetic macular oedema (DMO) from a multicentre database. Methods Structured clinical data were anonymised and extracted from an electronic medical record from 19 participating UK centres: age at first injection, ETDRS visual acuity (VA), number of injections, ETDRS diabetic retinopathy (DR) and maculopathy grade at baseline and visits. The main outcomes were change in mean VA from baseline, number of injections and clinic visits and characteristics affecting VA change and DR grade. Results Data from 12 989 clinic visits was collated from baseline and follow-up for 3103 eyes. Mean age at first treatment was 66 years. Mean VA (letters) for eyes followed at least 2 years was 51.1 (SD=19.3) at baseline, 54.2 (SD: 18.6) and 52.5 (SD: 19.4) at 1 and 2 years, respectively. Mean visual gain was five letters. The proportion of eyes with VA of 72 letters or better was 25% (baseline) and 33% (1 year) for treatment naïve eyes. Eyes followed for at least 6 months received a mean of 3.3 injections over a mean of 6.9 outpatient visits in 1 year. Conclusions In a large cohort of eyes with DMO treated with ranibizumab injections in the UK, 33% of patients achieved better than or equal to 6/12 in the treated eye at 12 months compared with 25% at baseline. The mean visual gain was five letters. Eyes with excellent VA at baseline maintain good vision at 18 months.