Adnan Tufail

Repeatability of manual subfoveal choroidal thickness measurements in healthy subjects using the technique of enhanced depth imaging optical coherence tomography.

PURPOSE The aim of this study was to investigate the repeatability of manual measurements of choroidal thickness in healthy subjects imaged on spectral domain optical coherence tomography (OCT) using the enhanced depth imaging (EDI) technique. METHODS Fifty consecutive, healthy, young, adult volunteers with no known eye disease were enrolled prospectively. Two good-quality horizontal and vertical line scans through the fovea were obtained for each eye. Using the manual calipers provided by the software of the proprietary device, two experienced OCT readers measured the subfoveal choroidal thickness (SFCT) of the horizontal and vertical line scans for all eyes. The readers were masked to each others readings. Intraobserver, interobserver, and intrasession coefficients of repeatability (CRs) were calculated. RESULTS Mean (standard deviation [SD]) age of the study subjects was 38 (5) years (range, 30-49 years). Mean (SD) subfoveal choroidal thickness was 332 (90) μm (right eyes) and 332 (91) μm (left eyes). Intraobserver CR was approximately 23 (95% confidence interval [CI], 19-26) μm, whereas interobserver and intrasession CRs were greater at 32 (95% CI, 30-34) and 34 (95% CI, 32-36) μm, respectively. There was no significant difference in SFCT between all pairs of SFCT measurements except for the two intrasession vertical line scans. CONCLUSION A change of >32 μm was likely to exceed interobserver variability in SFCT. Future studies are required to estimate the repeatability of SFCT measurements in patients with chorioretinal pathology.

Bevacizumab for neovascular age related macular degeneration (ABC Trial): multicentre randomised double masked study.

Objectives To evaluate the efficacy and safety of intravitreous bevacizumab injections for the treatment of neovascular age related macular degeneration. Design Prospective, double masked, multicentre, randomised controlled trial. Setting Three ophthalmology centres in the United Kingdom. Participants 131 patients (mean age 81) with wet age related macular degeneration randomised 1:1 to intervention or control. Interventions Intravitreous bevacizumab (1.25 mg, three loading injections at six week intervals followed by further treatment if required at six week intervals) or standard treatment available at the start of the trial (photodynamic treatment with verteporfin for predominantly classic type neovascular age related macular degeneration, or intravitreal pegaptanib or sham treatment for occult or minimally classic type neovascular age related macular degeneration). Main outcome measures Primary outcome: proportion of patients gaining ≥15 letters of visual acuity at one year (54 weeks). Secondary outcomes: proportion of patients with stable vision and mean change in visual acuity. Results Of the 131 patients enrolled in the trial, five patients did not complete the study because of adverse events, loss to follow-up, or death. In the bevacizumab group, 21 (32%) patients gained 15 or more letters from baseline visual acuity compared with two (3%) in the standard care group (P<0.001); the estimated adjusted odds ratio was 18.1 (95% confidence interval 3.6 to 91.2) and the number needed to treat was 4 (3 to 6). In addition, the proportion of patients who lost fewer than 15 letters of visual acuity from baseline was significantly greater among those receiving bevacizumab treatment (91% (59) v 67% (44) in standard care group; P<0.001). Mean visual acuity increased by 7.0 letters in the bevacizumab group with a median of seven injections compared with a decrease of 9.4 letters in the standard care group (P<0.001), and the initial improvement at week 18 (plus 6.6 letters) was sustained to week 54. Among 65 patients treated with bevacizumab, there were no cases of endophthalmitis or serious uveitis related to the intervention. All end points with respect to visual acuity in the study eye at 54 weeks favoured bevacizumab treatment over standard care. Conclusions Bevacizumab 1.25 mg intavitreous injections given as part of a six weekly variable retreatment regimen is superior to standard care (pegaptanib sodium, verteporfin, sham), with low rates of serious ocular adverse events. Treatment improved visual acuity on average at 54 weeks. Trial registration number Current controlled trials ISRCTN83325075

Evaluation of Age-related Macular Degeneration With Optical Coherence Tomography

Age-related macular degeneration (AMD) is the leading cause of severe visual loss in people aged 50 years or older in the developed world. In recent years, major advances have been made in the treatment of AMD, with the introduction of anti-angiogenic agents, offering the first hope of significant visual recovery for patients with neovascular AMD. In line with these advances, a new imaging modality-optical coherence tomography (OCT)-has emerged as an essential adjunct for the diagnosis and monitoring of patients with AMD. The ability to accurately interpret OCT images is thus a prerequisite for both retina specialists and comprehensive ophthalmologists. Despite this, the relatively recent introduction of OCT and the absence of formal training, coupled with rapid evolution of the technology, may make such interpretation difficult. These problems are compounded by the phenotypically heterogeneous nature of AMD and its complex morphology as visualized using OCT. We address these issues by summarizing the current understanding of OCT image interpretation in patients with AMD and describe how OCT can best be applied in clinical practice.

Large-scale remapping of visual cortex is absent in adult humans with macular degeneration

The occipital lobe contains retinotopic representations of the visual field. The representation of the central retina in early visual areas (V1–3) is found at the occipital pole. When the central retina is lesioned in both eyes by macular degeneration, this region of visual cortex at the occipital pole is accordingly deprived of input. However, even when such lesions occur in adulthood, some visually driven activity in and around the occipital pole can be observed. It has been suggested that this activity is a result of remapping of this area so that it now responds to inputs from intact, peripheral retina. We evaluated whether or not remapping of visual cortex underlies this activity. Our functional magnetic resonance imaging results provide no evidence of remapping, questioning the contemporary view that early visual areas of the adult human brain have the capacity to reorganize extensively.

Test-Retest Variability of Microperimetry Using the Nidek MP1 in Patients with Macular Disease

PURPOSE To determine the test-retest variability of the retinal sensitivity of the Nidek MP1 microperimeter in patients with macular disease. METHODS In this prospective study, 50 patients were enrolled with a range of macular diseases. One examiner performed two consecutive microperimetry tests for all patients using the same test strategy. Test-retest variability for mean sensitivity (MS), mean deviation (MD), point-wise sensitivity (PWS), local defect classification (LDC), average sensitivity for the central macula (CMS, 16 loci inside 10 degrees ), paracentral macular sensitivity (PMS, 52 loci in the 10 to 20 degrees ring), and dense scotoma size (DSS) were analyzed by calculating the 95% coefficients of repeatability or percentage agreement. RESULTS Mean (SD) age and visual acuity were 61 (15) years and 0.34 (0.32) logMAR, respectively. The mean difference in MS between tests 1 and 2 was +0.2 dB (SD, 0.9 dB; P = 0.127). The coefficients of repeatability for MS, MD, CMS, and PMS were 1.81, 2.56, 2.13, and 1.93 dB, respectively. The mean (SD) of coefficients of repeatability for PWS across all 68 loci was 5.56 (0.86) dB. Of all test loci in all patients 76% had perfect agreement in LDC, and 94% of patients had a change in DSS of four or fewer test loci. CONCLUSIONS Test-retest variability was lowest for MS and highest for PWS. However, MS does not provide spatial information. The authors recommend the use of CMS and PMS for monitoring macular function and consider a change of greater than 2.56 and 2.31 dB (the upper limit of the 95% confidence interval of their coefficients of repeatability), respectively, to exceed test-retest variability.

Persistently culture positive acanthamoeba keratitis: In vivo resistance and in vitro sensitivity

PURPOSE To characterize the risk factors, clinical course, treatment outcome and the association between in vivo resistance and in vitro sensitivity for subjects with persistently culture-positive Acanthamoeba keratitis. DESIGN Retrospective noncomparative case series. PARTICIPANTS Eleven subjects with repeatedly positive cultures for Acanthamoeba treated between January 1990 and December 2000, were reviewed. Only subjects with 2 or more positive cultures, availability of the clinical data, and availability of the last Acanthamoeba isolate were included in this study. METHODS The medical records were analyzed, and the last isolate from each case was tested in vitro for the antiamoebic drugs used clinically: polyhexamethylene biguanide (PHMB), chlorhexidine, propamidine and hexamidine. MAIN OUTCOME MEASURES Risk factors, the clinical outcome and in vitro cysticidal drug sensitivity assay. RESULTS Eleven subjects (11/180, 6.1%) had 2 or more positive cultures of whom 8 eyes of 8 subjects (8/180, 4.45%) were included in this study. Seven of eight (87%) subjects were diagnosed over 1 month from onset (late diagnosis). The most common presenting findings were diffuse stromal infiltrate (5/8, 62.5%), ring infiltrate (5/8, 62.5%), and corneal ulceration (3/8, 37.5%). The clinical course of the disease in all subjects consisted of recurrent episodes of corneal and scleral inflammation, with a mean duration of 13.4 +/- 9 months. All subjects received PHMB, and 5/8 (62.5%) chlorhexidine too; hexamidine was used in combination in 6/8 (75%), and propamidine in 1/8 (12.5%). All subjects had topical steroids, and 5/8 (62.5%) systemic immunosuppression. The disease resolved with corneal scarring in 3/8 (37.5%) subjects, corneal (or impending) perforation treated with therapeutic keratoplasty in 4/8 (50%), and enucleation in 1/8 (12.5%). Final visual acuity was 0.43 +/- 0.37. In vitro most isolates were resistant to propamidine, hexamidine was cysticidal in high concentrations, and PHMB and chlorhexidine had excellent sensitivity profiles. CONCLUSIONS In our large series of Acanthamoeba keratitis with a positive microbiologic diagnosis at presentation, nearly 5% developed recurrent episodes of corneal and scleral inflammation with viable Acanthamoeba in the cornea despite prolonged treatment with biguanides and/or diamidines. There was no correlation between in vitro drug sensitivities and the in vivo response for biguanides.

Evaluation of Autofluorescence Imaging with the Scanning Laser Ophthalmoscope and the Fundus Camera in Age-related Geographic Atrophy

PURPOSE To compare fundus autofluorescence images (FAF) between a modified fundus camera (mFC) and a confocal scanning laser ophthalmoscope (cSLO). DESIGN Evaluation of diagnostic technology. METHODS Thirty-two eyes of 16 patients with age-related geographic atrophy (GA) treated in an institutional setting were included. FAF images were obtained with both the cSLO (excitation, 488 nm; emission, > 500 nm) and the mFC (excitation, approximately 500 to 610 nm; emission, approximately 675 to 715 nm). Using established algorithms, images were graded by two independent observers and agreements were evaluated. The main outcome measures were image quality, quantification of total atrophy, and classification of FAF patterns. RESULTS In two eyes with advanced cataract (lens grade 7 according to the Age-Related Eye Disease Study classification), FAF image quality with both systems was not sufficient for any meaningful analysis. In the remaining 30 eyes, the mean differences of the interobserver agreements for atrophy quantification were 0.16 mm2 (95% confidence interval [CI], 0.07 to 0.38) for mFC and 0.15 mm2 (95% CI, -0.04 to 0.33) for cSLO images. Because of inferior signal-to-noise ratios, FAF pattern classification was possible in a lower number of mFC images (69%) compared with cSLO images (88%). CONCLUSIONS This study suggests that the agreements for atrophy quantification are similar with both devices. The lesser visualization of FAF patterns with the mFC and thus inferior determination of disease markers may be the result of the nonconfocality and the use of single instead of mean images compared with the cSLO. These findings may be important for the design of interventional trials as well as the routine use of FAF imaging in age-related geographic atrophy.

Myopic choroidal neovascularisation: current concepts and update on clinical management

Choroidal neovascularisation (CNV) is a common vision-threatening complication of myopia and pathological myopia. Despite significant advances in understanding the epidemiology, pathogenesis and natural history of myopic CNV, there is no standard definition of myopic CNV and its relationship to axial length and other myopic degenerative changes. Several treatments are available to ophthalmologists, but with the advent of new therapies there is a need for further consensus and clinical management recommendations. Verteporfin photodynamic therapy has been an established treatment for subfoveal myopic CNV for many years, but this treatment does not restore visual acuity and is associated with long-term chorioretinal atrophy. More recently, clinical trials investigating the efficacy and safety of anti-vascular endothelial growth factor agents in patients with myopic CNV have demonstrated substantial visual acuity gains and quality of life increases compared with photodynamic therapy. These enhanced outcomes provide updated evidence-based clinical management guidelines of myopic CNV, and increase the need for a generally accepted definition for myopic CNV. This review critically summarises the latest myopic CNV literature in the context of clinical experience and recommends a myopic CNV treatment algorithm.

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.

Topographic Variation and Interocular Symmetry of Macular Choroidal Thickness Using Enhanced Depth Imaging Optical Coherence Tomography

PURPOSE To report and analyze factors influencing topographical and interocular variations in choroidal thickness (CT) in a healthy adult population. METHODS One hundred eyes of 50 healthy subjects underwent visual acuity and axial length measurements and optical coherence tomography (OCT) with enhanced depth imaging (EDI). CTs at the fovea and at 3 mm nasal, temporal, superior, and inferior to the fovea were measured manually. Topographic variation, relative interocular differences in CT and predictors of CT were analyzed. The relationships between interocular differences in CT and differences in age and interocular axial length were explored. RESULTS The mean (SD) foveal CT in the right and left eyes were 334 (95) and 333 (90) μm, respectively. For foveal CT, there was a high correlation between the two eyes (r = 0.90) with a relative interocular 95% limits of agreement of -80 to +83, and a median (range) absolute difference of 21 (0.4-135). There was no significant variation in the relative and absolute interocular differences in CT. Axial length was the main predictor of CT for nasal and foveal CT. Symmetry in CT in the horizontal and vertical meridians was seen in eyes with axial length shorter than 23.50 mm (P < 0.05). CONCLUSIONS There was no significant relative interocular difference in CT. Axial length contributes to some of the variances in CT but has a significant influence on the CT profile. Although relative interocular difference is not significant, absolute interocular differences in CT may reach 85 μm.