The Effect of Multispot Laser Panretinal Photocoagulation on Retinal Sensitivity and Driving Eligibility in Patients with Diabetic Retinopathy

Supplementary Online Content

Subash M, Comyn O, Samy A, et al. The effect of multispot laser panretinal photocoagulation on retinal sensitivity and driving eligibility in patients with diabetic retinopathy. JAMA Ophthalmol. Published online April 14, 2016. doi:10.1001/jamaophthalmol.2016.0629.

eMethods. Laser Treatment Variables, Assessments, and Retinal Imaging

eResults. Laser Treatment and Secondary Outcomes

eTable 1. Cross Tabulation of Baseline Clinical Diabetic Retinopathy Grade of the Enrolled Participants

eTable 2. Retinal Sensitivity Results From Microperimetry for Central Macular 12° and 4°

eTable 3. Cross Tabulation of Early Treatment Diabetic Retinopathy Study Grade of Retinopathy in Right and Left Eyes for Each Subject at Baseline and Exit

This supplementary material has been provided by the authors to give readers additional information about their work.

Downloaded From: https://jamanetwork.com/ on 10/01/2021 eMethods

All subjects underwent standard clinical examination including Early Treatment Diabetic Retinopathy Study (ETDRS) best-corrected visual acuity (BCVA), slit-lamp and fundus biomicroscopy and macular spectral domain optical coherence tomography (SDOCT) at every visit. A full medical history, glycosylated hemoglobin level, intraocular pressure measurements and cataract status were recorded at baseline and exit as possible confounding factors for visual acuity and visual field test assessment.

Laser Treatment Variables

1. Actual retinal spot size 400μm. 2. 1000 to 1200 burns per eye per session (If patients were unable to tolerate 1000 burns per eye or bilateral laser treatment they returned for treatment within 1 week). 3. Pulse duration of 20ms. 4. Spot separation of 1 burn width. 5. Power sufficient to achieve "blanching" (i.e. a greyish white lesion) of the retina without producing visible necrosis. 6. Grid array – 2x2, 3x3 or 4x4.

All subjects underwent two initial treatment sessions of up to 1200 burns per eye per session. The two sessions were separated by 2 weeks with the aim of delivering approximately 2400 burns during this first phase of laser therapy. Subsequent review occurred at 6 weekly intervals unless clinically indicated to be a shorter interval. In the presence of persistent active retinopathy, a further 800-1200 burns were undertaken. Laser was continued until treatment completion was reached or efficacy was determined on clinical grounds with one or more of the following markers in the presence of adequate laser coverage and retinal reaction:

i) Regression of neovascularization (defined as complete resolution of neovascularization at the disc or elsewhere, or significant reduction in size or caliber); ii) Absence of leakage on fundus fluorescein angiography; iii) Development of fibrosis.

Visual Field and Retinal Functional Assessments

For all static perimetry, white stimulus size III was used on a background of 10 cd/m2. The stimulus duration was 200 ms. In order to maximize co-operation, accuracy and minimize fatigue, clear standardized instructions were provided by the perimetrist at every perimetry session to all subjects and breaks were taken between eyes and during testing if needed. The patient’s refractive error was corrected for perimetry testing. Binocular Esterman Visual Field Test If at the end of the binocular Esterman visual field test more than 20% false positives were recorded, the test was repeated prior to continuing with monocular static testing. The visual fields were assessed in accordance with UK standards for Group 1 (car) driving eligibility by a study investigator (MS) and adjudicated by an ophthalmologist who is Chairman of the Honorary Medical Advisory Panel to the Secretary of State on Visual Disorders and Driving (AV). Full Field Static Testing on Octopus 900 The custom monocular grid developed by Richard Weleber (co-author) for the Octopus 900 was the 138- point Monocular DM GATE III. The binocular full field static test used was the 120-point Esterman grid. If the reliability factor was more than 19 for either the mono- or binocular tests then the test was repeated. In addition to refractive correction, we followed the Octopus 900 guidelines for additional correction for presbyopia, which was titrated to age. The perimetrist monitored and encouraged maintenance of fixation rather than have EyeSuite perform this function, which can lengthen the test. Computation of volumetric “hill-of-vision” data Data representing test locations and associated sensitivity data in dB were exported to Visual Field Modeling and Analysis Software. These sensitivity data were fit to a thin-plate spline, allowing the creation

Downloaded From: https://jamanetwork.com/ on 10/01/2021 of a three-dimensional model of the entire hill-of-vision (HoV). From this can be calculated the sensitivity volume in decibel-steradian (dB-sr), by integration of the sensitivity of the visual field with the solid angle beneath the envelope. The unit dB-sr thereby represents the volume of the HoV, and in doing so quantifies both magnitude and extent, to allow more accurate and sensitive measurement of change over time. 1 Kinetic Monocular Goldmann Perimetry The stimulus test targets used were V4e, III4e, and I4e. The blind spot was checked with I4e (or the next largest stimulus size if patient was unable to see). The vectors were checked at least every 30° and six reaction time vectors were checked with III4e (or V4e if patient was unable to see) in healthy areas of vision. The perimetrist judged and made written comments on cooperation and reliability. The areas of the plotted isopters of the 3 stimuli were digitalized and calculated using custom computer software (Retinal analysis tool; Halfyard and Fitzke, UCL Institute of Ophthalmology, London, UK). The program enabled the tracing of the blind spot for calibration and then the contours of the plotted isopters to calculate the areas.

Microperimetry Mesopic microperimetry was performed using the MP-1 microperimeter in a darkened room on subjects without macular edema or planned macular laser treatment. All subjects were dark-adapted for 10 minutes prior to commencing the test. We used a customized 45-point radial grid covering the central 12 degrees of the macula for mean retinal sensitivity recording with a testing stimulus size of Goldmann III (4 mm2) of 200ms duration. The MP-1 incorporated an automatic tracking system to compensate for eye movement for accurate stimulus projection during the examination. Fixation was assessed for location and stability automatically by the MP-1 machine using the bivariate contour ellipse area (BCEA) method, which represents an area in degrees where 68% (one standard deviation) of fixation points are located.

Questionnaire Subjects completed the Massof Activity Inventory, an adaptive visual function questionnaire, at baseline and six months.

Retinal Imaging

After pupillary dilation with tropicamide (1%) and phenylephrine (2.5%) eye drops, subjects underwent a number of structural imaging studies, repeated at exit: Ultra-widefield Color and Fluorescein Fundus Photography Color optomap photos were obtained using the ultra-widefield camera (Optos, Dunfermline, UK). Images for each eye were taken on axis 200°. Following bolus intravenous injection of 5 mls sodium fluorescein 20%, angiographic images of both eyes were captured at predefined time-points for 200° and 100° ResMax axes. Inferior and superior retinal steered images were captured if the retina was not visible beyond 70° due to heavy eyelids or eyelashes. Images were analyzed by the Moorfields Eye Hospital Reading Centre. A mask was applied to the widefield image to report ETDRS grade from the standard seven-field area. With the mask removed, retinopathy grade was re-evaluated including information from the mid to far periphery. This was done at baseline and six months by a trained and certified senior diabetic retinopathy grader (TM) who grades for diabetic retinopathy and maculopathy full-time. This grader achieves over 90% on the monthly test and training set for diabetic retinopathy on an image set graded by all diabetic retinopathy screening graders in England (currently over 1000 people grading per month). Re-grading of randomly selected images by the clinical lead (TP) took place 14 days after initial grading. There was only one set of images where there was disagreement on the level of diabetic retinopathy: a set of images with a small new vessel complex that was difficult to grade for size. From color and angiographic images the Reading Centre also graded coverage of retinal laser burns at 6 months and reported the presence of macular ischemia, defined as foveal avascular zone greatest linear dimension of more than 1000µm or severe perifoveal capillary loss. ETDRS grade 60 (presence of old PRP scars) was not utilised in the grading at six months, to allow better reporting of changes in non-proliferative features of retinopathy in the presence of laser scars. Spectral Domain OCT Line and volume scans from both eyes were obtained using a Spectralis SDOCT device (Heidelberg Engineering GmbH, Heidelberg, Germany). The volume acquisition protocol consisted of 49 B-scans (124μm between scans; 20° x 20°), with Automatic Real Time eye tracking used whenever possible. A

Downloaded From: https://jamanetwork.com/ on 10/01/2021 follow-up mode was achieved and adopted by setting the baseline scan as the reference scan, which enabled the inbuilt software to direct the SDOCT laser to the same retinal location during subsequent image acquisition. Automated retinal thickness measurements have been shown to be highly reproducible2 and were used to acquire macular thickness and volume measurements in the nine ETDRS subfields.

Downloaded From: https://jamanetwork.com/ on 10/01/2021 eResults. Laser Treatment and Secondary Outcomes

Laser Treatment One hundred and eighty-five visits for planned laser treatment took place in total. In 120 of these PRP was applied to both eyes, in 47 visits PRP to one eye only, and in 18 occasions no laser treatment was applied due to vitreous hemorrhage, patient request to postpone treatment, fully treated disease, or anterior uveitis (one case). The median number of visits required to achieve full PRP laser in both eyes was 4 (interquartile range (IQR) 2).

Laser treatment was applied with a Volk Superquad 160 contact lens in all subjects. In the right eye, the median (IQR) power used was 398.5 (123) mW and median (IQR) total energy 6.5 (5) Joules (J). For the left eye, median (IQR) power and energy were 350 (38) mW and 6.5 (5) J respectively. A median (IQR) of 3144 (1213) burns were applied for the right eye and 3067 (1304) to the left.

Nine macular laser treatments were given during the study, with four eyes at baseline having clinically significant macular edema (CSME) compared with seven at exit. Laser was delivered using a Volk Area Centralis lens, spot size of 50-100 µm and power of 100-190 mW, sufficient to cause a barely visible blanching of the retinal pigment epithelium in the region of microaneurysms and in areas of visible retinal thickening. The mean number of burns per macular laser was 64.6.

Using the aforementioned clinical definitions (eMethods) there was evidence of clinically significant response to PRP at exit in 31 subjects (31/38; 82%)

Secondary Outcomes Microperimetry Microperimetry was conducted in a subset of patients (n=35 at baseline, n=33 at six months) ; reasons for not testing were predominantly fatigue and also the presence of clinically significant macular edema. The macular 12 degree and 4 degree mean retinal sensitivity was relatively stable following PRP at 6 months from initial visit (eTable 2).

Best-Corrected Visual Acuity and Central Macular Thickness Mean (SD) BCVA at baseline was 81 (9) ETDRS letters (Snellen equivalent 20/25) for the right eye and 80 (10) for the left (Snellen: 20/25); and right eye was 80 (9) and left eye 78 (12) letters (Snellen: 20/32) at six months. There was a clinically non-significant increase in central macular thickness from 282 (43) µm to 290 (58) µm in the right eye and from 272 (39) µm to 299 (98) µm in the left.

Reading Center Diabetic Retinopathy Grading At baseline, 37 of 39 subjects with gradable images in both eyes had severe non-proliferative diabetic retinopathy in both eyes, severe non-proliferative retinopathy in one eye with proliferative retinopathy in the other, or proliferative retinopathy in both eyes. Two subjects had proliferative retinopathy in one eye but were graded by the Reading Centre as having moderately severe non-proliferative retinopathy in the other. eTable 3 shows the numerical Early Treatment Diabetic Retinopathy study grade in the right and left eye for each subject. Grading of the mid to far periphery did not change the overall retinopathy grade in any subject. At the six month exit visit, 34 subjects had gradable images from both eyes. Despite the high number graded as still having proliferative retinopathy, evaluation by the Reading Centre found that 23 (68%) of the 34 subjects graded demonstrated stable diabetic retinopathy following laser treatment and a further 2 (6%) had stable retinopathy but developed clinically significant macular edema.

Macular ischemia Reading Centre evaluation of completed fluorescein angiograms at baseline (n=39) for macular ischemia revealed an enlarged foveal avascular zone in nine eyes and at exit in eight eyes (n=25). Eight eyes had severe perifoveal capillary loss at baseline and 13 at exit.

Retinal Laser Burn Coverage Widefield images were graded for laser burn coverage using a six-point semi-continuous scale by the Reading Centre at the exit visit (table 8). Two grades were reported; in an area measuring 2x2 disc

Downloaded From: https://jamanetwork.com/ on 10/01/2021 diameters lying nasal to the optic disc, and the entire visible field. In the 2x2 area the modal value for laser coverage was 1, representing 1-25% burn coverage. Over the entire field, the modal value was 3, representing 50-75% burn coverage.

Questionnaire The mean score from the Massof Activity Inventory questionnaire at baseline was 17.6 (n=23) and at exit had reduced to 16.4 (P=0.6). Rasch analysis was applied to assign weights to each score and then to average the weighted measures. The mean difference between measures at baseline and six months was then 0.002 (SEM 0.33, P>0.99).

Safety Outcomes The ocular adverse events reported included self-resolving ocular pain (4 subjects) and self-resolving bilateral photopsia (2 subjects) following laser treatment. One subject underwent indirect PRP under sub- Tenon’s anesthetic during the study due to poor pain threshold for adequate slit-lamp delivery of laser. Another subject had their follow-up laser treatment deferred due to acute anterior uveitis, which resolved with topical treatment and did not impact further laser treatments or the course of the diabetic retinopathy. Six subjects had deferred laser treatment due to vitreous hemorrhage precluding adequate retinal views, which was attributed to the natural course of the disease. No non-ocular adverse events were reported. In six patients who failed to attend follow-up visits despite multiple attempts at contacting them, diabetic retinopathy progressed during the study due to inadequate laser treatment. Three of these patients required vitrectomy/delamination surgery.

References

1. Weleber RG, Smith TB, Peters D, et al. VFMA: Topographic Analysis of Sensitivity Data From Full-Field Static Perimetry. Transl Vis Sci Technol. Apr 2015;4(2):14. 2. Comyn O, Heng LZ, Ikeji F, et al. Repeatability of Spectralis OCT Measurements of Macular Thickness and Volume in Diabetic Macular Edema. Invest Ophthalmol Vis Sci. Dec 2012;53(12):7754-7759.

Downloaded From: https://jamanetwork.com/ on 10/01/2021 eTable 1. Cross Tabulation of Baseline Clinical Diabetic Retinopathy Grade of the Enrolled Participants

Retinopathy grade Retinopathy grade Left eye Right eye Severe NPDR Low risk PDR High risk PDR Severe NPDR 3 2 1 Low risk PDR 4 20 1 High risk PDR 0 3 9

PDR - proliferative diabetic retinopathy; NPDR – non-proliferative diabetic retinopathy. Participants are enrolled in a study to evaluate laser photocoagulation on retinal sensitivity in proliferative diabetic retinopathy. Two left eyes and two right eyes had clinically significant macular edema.

Downloaded From: https://jamanetwork.com/ on 10/01/2021 eTable 2. Retinal Sensitivity Results From Microperimetry for Central Macular 12° and 4°

Baseline 6 months n Mean Sensitivity n Mean Sensitivity Mean Change (dB) (dB) (dB)

12 ° Right eyes 31 16.2 (3.4) 32 14.8 (3.9) -1.6 (2.8) 12 ° Left eyes 30 16.8 (3.2) 30 14.7 (4.6) -2.4 (3.9) 4 ° Right eyes 35 15.2 (4.0) 33 12.6 (6.6) -3.0 (5.2) 4 ° Left eyes 34 15.4 (4.6) 29 13.1 (6.3) -2.6 (5.4)

Subjects received panretinal photocoagulation in a study of its effect on visual fields and retinal sensitivity. Data presented as mean (standard deviation). dB – decibels.

Downloaded From: https://jamanetwork.com/ on 10/01/2021 eTable 3. Cross Tabulation of Early Treatment Diabetic Retinopathy Study Grade of Retinopathy in Right and Left Eyes for Each Subject at Baseline and Exit

Baseline RE LE 43 47 53 61 65 71 75 81   43 1 47 1 53 3 1 1 61 2 3 1 65 2 2 9 1 71 1 4 2 75 2 2 81 1

Exit RE LE 43 47 53 61 65 71 75 81 85   43 2 1 47 53 1 61 1 1 4 1 65 1 7 2 71 1 5 2 75 1 2 81 1 1 85

Results shown as numerical Early Treatment Diabetic Retinopathy Study grade for each of 39 subjects at baseline and 34 subjects at exit with gradable images in both eyes using wide-field color fundus photographs from a study evaluating the effect of panretinal photocoagulation on visual fields and driving. RE – right eye, LE – left eye

Non-proliferative diabetic retinopathy both eyes Non-proliferative diabetic retinopathy one eye, proliferative diabetic retinopathy other eye Proliferative diabetic retinopathy both eyes

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