Barely Visible 10-Millisecond Pascal Laser ...

Barely Visible 10-Millisecond Pascal Laser Photocoagulation for Diabetic Macular Edema: Observations of Clinical Effect and Burn Localization MAHIUL M. K. MUQIT, JANE C. B. GRAY, GEORGE R. MARCELLINO, DAVID B. HENSON, LORNA B. YOUNG, NIALL PATTON, STEPHEN J. CHARLES, GEORGE S. TURNER, AND PAULO E. STANGA ● PURPOSE: To investigate the morphologic features and clinical efficacy of barely visible Pascal (Optimedica Corporation) photocoagulation burns in diabetic macular edema (DME) using Fourier-domain optical coherence tomography (FD OCT) and fundus autofluorescence (AF). ● DESIGN: Interventional case series. ● METHODS: Retrospective evaluation of 10 eyes with newly diagnosed DME that underwent barely visible Pascal photocoagulation using an array of 10-␮m, 10-millisecond photocoagulation burns. FD OCT and camera-based AF was performed at baseline and at 1 hour, 2 weeks, 4 weeks, and 12 weeks after laser. Changes in retinal thickening after laser treatment were measured using retinal thickness maps within the treated sector and the central foveal subfield. ● RESULTS: At 1 hour after treatment, burns were visualized partially with clinical biomicroscopy. AF demonstrated spots lacking autofluorescence that confirmed effective laser uptake within the Pascal arrays. Sequential changes in hyperreflectivity on FD OCT correlated with morphologic alterations seen on AF. Burns became increasingly hyperautofluorescent between 2 and 4 weeks. There were significant reductions in the retinal thickness within treated sectors on FD OCT at 2 weeks (26 ⴞ 32 ␮m; P ⴝ .012) and 3 months after laser (20 ⴞ 21 ␮m; P ⴝ .02) compared with baseline. Clinical biomicroscopic reduction of DME was the most common finding in 80%. ● CONCLUSIONS: Barely visible 10-millisecond Pascal laser seems to produce an effect at the level of the inner and outer photoreceptor segments and apical retinal pigment epithelium, with minimal axial and lateral spread of burns. FD OCT confirmed spatial localization of AF signal changes that correlated with laser burn–tissue interactions over 3 months. The technique of lowerfluence barely visible 10-millisecond laser may reduce retinal edema within affected sectors and effectively treat DME with minimization of scar formation. (Am J Accepted for publication Jan 25, 2010. From the University of Manchester, Manchester Royal Eye Hospital, Manchester, United Kingdom (M.M.K.M., D.B.H., P.E.S.); the Department of Clinical Imaging (J.C.B.G.), Diabetic Screening Service (L.B.Y.), Vitreoretinal Service (N.P., S.J.C., G.S.T., P.E.S.), Manchester Royal Eye Hospital, Manchester, United Kingdom; and OptiMedica Corporation, Santa Clara, California (G.R.M.). Inquiries to Paulo E. Stanga, Manchester Royal Eye Hospital, Oxford Road, Manchester, M139WH, United Kingdom; e-mail: retinaspecialist@ btinternet.com 0002-9394/$36.00 doi:10.1016/j.ajo.2010.01.032

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D

IABETIC MACULAR EDEMA (DME) REMAINS THE

most common cause of visual loss in diabetic patients. The Early Treatment Diabetic Retinopathy Study (ETDRS) reported both the efficacy of visible end-point laser burns placed in a grid pattern up to the edge of the fovea and the focal photocoagulation of microaneurysms in DME.1 The ETDRS demonstrated that immediate photocoagulation with gray-white burns reduced moderate visual loss by 50% (from 24% to 12%) 3 years after initiation of treatment. However, after 12 months, 40% of treated patients had persistent DME with associated visual loss. It is well recognized that conventional (long duration, 100 milliseconds) laser scar expansion in the macula may be associated with enlarging atrophy of the retinal pigment epithelium (RPE) and paracentral scotomas over time.2,3 Controversy remains as to whether a reduction in laser fluence may continue to treat macular edema effectively secondary to diabetic retinopathy. Barely visible (light gray, threshold) laser burns using a conventional long-pulse argongreen laser have been investigated in comparison with ETDRS gray-white photocoagulation burns in case series. Bandello and associates reported effective treatment of DME in the long term with threshold laser power.4 However, in a larger randomized study, the effect of mild macular grid conventional laser was not shown to be significantly more effective than modified ETDRS treatment methods.5 The modified ETDRS technique has recommended barely visible (light gray, threshold) burn intensity for conventional 50millisecond macular laser photocoagulation. The Writing Committee for the Diabetic Retinopathy Clinical Research Network stated, “In an attempt to reduce these adverse effects, many retinal specialists now treat patients using burns that are lighter and less intense than what was originally specified in the ETDRS.”5 Recent methods such as selective retina therapy report therapeutic effects using ultrashort pulse durations.6 Micropulse and subthreshold photocoagulation have been reported to produce equally effective or improved visual outcomes than standard modified ETDRS laser treatment.7,8 However, the absence of visible laser uptake may

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TABLE. Diagnostic and Pascal Laser Parameters for Diabetic Macular Edema

Eye

DME OCT Subtype

Pascal Laser Array

Energy Power (mW)

Energy Fluence (J/cm2)

Pulse Duration (ms)

Spot Size (␮m)

Clinical Regression in DME

1 2 3 4 5 6 7 8 9 10

SP SP/CYST SP SP SP/CYST SP/CYST SP SP SP SP

FM-DO FG FM-SO FM-SO HSG FG FM-SO HSG FM-SO FG

125 125 125 100 100 150 100 150 150 125

16 16 16 13 13 19 13 19 19 16

10 10 10 10 10 10 10 10 10 10

100 100 100 100 100 100 100 100 100 100

Yes Yes Yes Yes No No Yes Yes Yes Yes

DME ⫽ diabetic macular edema; FG ⫽ full grid; FM-DO ⫽ focal macula double octant; FM-SO ⫽ focal macula single octant; HSG ⫽ horseshoe-shaped grid; OCT ⫽ optical coherence tomography; SP ⫽ sponge-like; SP/CYST ⫽ sponge-like with cystoid.

prompt inappropriate higher-power laser titration or unnecessary retreatment. The Pascal (pattern scanning laser; Optimedica Corporation, Santa Barbara, California, USA) photocoagulator is a semiautomated laser delivery system that reduces procedural time by delivering multiple laser burns within a single application.9 Importantly, medium pulse durations (10 milliseconds, 20 milliseconds) may result in less destruction to the outer retina, compared with conventional laser burns, presumably because of reduced axial and lateral thermal spread.10 Despite recent knowledge of the Pascal therapeutic parameters, benchmark laser parameters for treating DME have yet to be demonstrated in randomized clinical trials.11 Jain and associates reported threshold visible burns using 10-millisecond pulses in animal models.10 In clinical practice, it is important to image the in vivo effects of any lower fluence laser burns on human retina. This will ensure that laser photocoagulation is safe and that treatment may be better understood with monitoring over time. Our current practice involves the imaging of barely visible 10-millisecond photocoagulation burns with Fourier-domain optical coherence tomography (FD OCT) and fundus autofluorescence (AF) at different points in short-term postlaser treatment. This article reports on the location of 10-millisecond burns within outer retina and the effects of laser on the RPE–neuroretinal tissue over time with FD OCT. In DME, the morphologic effects of barely visible laser burns were examined retrospectively in relation to clinical effect and macular thickness with FD OCT and AF.

FIGURE 1. Analysis of retinal thickness in Patient 1 after a Fourier-domain optical coherence tomography scan was obtained 2 weeks after barely visible focal macular laser for diabetic macular edema. The average thickness within each of 9 Early Treatment Diabetic Retinopathy (ETDRS) sectors is shown within the circular grid. A shadowgram overlay has been inserted to demonstrate the laser burns that appear as dark spots within the inner and outer sectors of the superior, temporal, and inferior quadrants. The mean retinal thickness for this patient was calculated across 6 ETDRS sectors.

ment for sight-threatening DME and further analyzed these cases. All patients had given informed consent for treatment, and all investigations were performed as part of routine care at Manchester Royal Eye Hospital, Manchester, United Kingdom. Exclusion criteria for this sample of

METHODS ● SUBJECTS:

We retrospectively retrieved case notes for all patients who had undergone unilateral or bilateral barely visible 10-millisecond Pascal macular laser treat-

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FIGURE 2. Nine fundus autofluorescence (AF) images obtained 1 hour after barely visible laser (100 ␮m, 10 milliseconds) for diabetic macular edema. Laser burns within each Pascal array appear well demarcated as spots lacking autofluorescence on AF. The complete array of burns for single or multiple octants, horseshoe-shaped grid, and full-grid Pascal arrays are completely visualized.

subjects then included laser dosimetry that produced barely visible intensity burns (modified ETDRS light-gray grade) in all eyes, with no previous or repeated laser, medical, or surgical treatment performed. Exclusion criteria also included complete clinical and investigational data capture at the following follow-up visits: 1 hour after laser and at 2, 4, and 12 weeks after laser. Based on all stated exclusion criteria, we retrospectively identified and retrieved data for 10 eyes of 8 diabetic subjects who had undergone a single Pascal unilateral or bilateral macular laser treatment for DME, and these eyes then were studied. Digital fundus photography, FD OCT, and AF images were analyzed retrospectively. FD OCT and AF images were examined at 1 hour, 2 weeks, and 4 weeks to assess the laser uptake, the laser burn coverage at the macula, and the presence of intraretinal edema. Two experienced retina specialists (L.B.Y., P.E.S.) examined the amount of clinical thickening visible on biomicroscopy using either a Volk Digital High Mag lens (Volk Optical, Inc., Mentor, Ohio, USA) or Goldmann 3 mirror lens (Ocular Instruments, Bellevue, Washington, USA). Assessment of clinical effect was evaluated by the absence (positive clinical effect) or presence (negative clinical effect) of retinal thickening and edema on clinical biomicroscopy at 3 months after laser treatment. Additional clinical evaluation of macular edema involved comparison of prelaser and postlaser fundus color and red-free images to evaluate any changes in the number and extent of macular hard exudates. This was a retrospective VOL. 149, NO. 6

study of standard laser management, and the Greater Manchester Central Research Ethics Committee waived ethical approval for this work. This study adhered to the tenets of the Declaration of Helsinki. ● PASCAL PHOTOCOAGULATION SYSTEM:

This is a frequency-doubled neodymium:yttrium–aluminum– garnet solid-state laser with a wavelength of 532 nm. In full-grid treatment of DME, the A plus B pattern consisting of 4 concentric rings with 112 spots encircling the fovea was used. Each octant of the array contains 14 spots, and focal macular treatment comprised either single or multiple octants. To configure a horseshoe-shaped grid pattern, the supranasal and inferonasal octants are excluded to produce a total array of 84 spots.

● BARELY VISIBLE PASCAL TECHNIQUE: Each patient had undergone laser power titration within a macular zone below the superior arcade, as described in the following steps. A Mainster Focal contact lens was used, with a 100-␮m and 10-millisecond laser spot. Starting at 100 mW, power was increased in 25-mW steps until a visible (gray-white, modified ETDRS threshold) burn was produced. The power setting then was reduced by 25 mW (equivalent to fluence level of 3 J/cm2) that produced a barely visible burn. Patients received one of full grid, horseshoe-shaped grid, or focal macula arrays (Table). Microaneurysms routinely are not photocoagulated directly. Spot spacing within all arrays was equivalent to one

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FIGURE 3. Horizontal Fourier-domain optical coherence tomography scans of all 9 eyes obtained 1 hour after barely visible laser (100 ␮m, 10 milliseconds) for diabetic macular edema. Vertical bands of moderate reflectivity are visible within the outer retina. The hyper-reflectivity extends from the internal aspect of the outer highly reflective layer to involve the outer nuclear layer, with minimal extension to the outer plexiform layer. The inner retinal architecture and the outer aspect of the outer highly reflective layer have remained intact.

burn width. Immediately after laser application, all burns were barely visible clinically within each array.

internal limiting membrane, and the outer highly reflective layer within outer retina. The thin band of high reflectivity immediately internal to the outer highly reflective layer is believed to correspond to the junction between the inner segment and outer segment of the photoreceptors, and the outer highly reflective layer has been reported to represent the melanin in the RPE.15,16

● OCULAR IMAGING: Fundus Autofluorescence. We used a fundus flash-camera system (Topcon TRC-50DX, type IA; Topcon Instruments, Newbury, United Kingdom) to image AF in all cases. The AF exciter filter has a bandwidth of 30 nm and central wavelength of 580 nm with 60% transmission. The AF barrier filter has a bandwidth of 40 nm and a central wavelength of 695 nm. AF images show the spatial distribution of signal intensities for each pixel in gray values. Dark signals correspond to low pixel values and a lack of autofluorescence, and bright signals correlate with high pixel values and increased autofluorescence because of a window-type effect.12

● RETINAL THICKNESS MEASUREMENTS: Changes in retinal thickening after barely visible laser were measured using retinal thickness maps at all time points. Each macular map is divided automatically by the FD OCT software into 9 ETDRS sectors, and the analysis program automatically calculates the average thickness for each sector. The central 500 ␮m subfield is designated the foveal sector, with 4 inner and 4 outer rings comprising the other 8 sectors (Figure 1). The Pascal treatment arrays for all patients were extrapolated to the ETDRS map using shadowgram overlays and ETDRS grid within the 3-dimensional FD OCT analysis. For example, in Patient 1, Pascal focal macula treatment used 2 single octants to

Fourier-Domain Optical Coherence Tomography. FD OCT (Topcon, 3D OCT-1000) allows in vivo high-definition visualization of the retina.13,14 Important reflective signals include the inner highly reflective layer, which corresponds to the interface between the vitreous and the 982

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FIGURE 4. Serial fundus photography of Patient 7, who underwent focal, barely visible laser (100 ␮m, 10 milliseconds, 100 mW power, 13 J/cm2 fluence) for diabetic macular edema. Central retinal thickness (CRT) was 283 ␮m on optical coherence tomography (OCT) before laser treatment. At 1 hour after laser treatment, (Top left) color and (Center left) red-free fundus photographs showed nonvisible burns. (Bottom left) Fundus autofluorescence (AF) image at 1 hour demonstrating a single Pascal octant array, containing 14 laser burns with individual spots lacking autofluorescence. At 2 weeks, laser burns are partially visible on (Top middle) color and (Center middle) red-free photos. (Bottom middle) AF image obtained at 2 weeks showing laser burns with partial hyperautofluorescence. (Top right, Center right) Fundus photograph obtained at the 3-month visit showing nonvisible laser scars inferotemporal to the fovea. (Bottom right) AF image confirming partial autofluorescent signals confined to octant of barely visible laser burns. There is no significant expansion of burns, and the macular edema resolved on biomicroscopy. On OCT, final CRT was reduced to 264 ␮m. Snellen visual acuity remained stable at 6/6 over 3 months.

treat. The area of laser coverage was 6 ETDRS sectors, 3 inner and 3 outer sectors, because the foveal sector is not photocoagulated (Figure 1). The central retinal thickness (CRT) measurements were evaluated at baseline, 2 weeks, 4 weeks, and 3 months after laser treatment. We used the paired 2-tailed t test to explore changes in retinal thickness and Snellen visual acuity, and the null hypothesis was rejected for P values less than .05.

RESULTS A TOTAL OF 10 EYES OF 8 PATIENTS WITH DME TREATED WITH

barely visible laser were retrieved retrospectively (6 males, 2 females). Five eyes had diffuse DME and 5 had focal DME. Macular edema was classified using time-domain OCT before laser intervention: sponge-like (7/10 eyes) and sponge-like with cystoid (3/10 eyes).17 There were no cases of serous retinal detachment (Table). ● POSTOPERATIVE LASER PARAMETERS: After 1 hour, laser burns were partially visible within the treatment arrays using clinical biomicroscopy. AF imaging demonstrated spots lacking autofluorescence at 1 hour after laser treatment. Individual burns within the arrays were designated by spots lacking autofluorescence of uniform size and shape signal (Figure 2). In all eyes, hyperautofluorescent laser spots were

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visible after 2 weeks within the treatment arrays. On color and red-free fundus photography, laser burns were not completely visible. Hyperautofluorescence remained present at 4 weeks in all eyes. Using FD OCT at 1 hour, small vertical bands of moderate reflectivity extended from the internal aspect of the outer highly reflective layer to involve the outer nuclear layer, with minimal extension to the outer plexiform layer.18 The inner retinal architecture remained intact. The outer aspect of the outer highly reflective layer showed no signs of injury, and there were no clinical signs of intraretinal or subretinal hemorrhage. This vertical band of moderate reflectivity corresponded to individual barely visible laser burns (Figure 3). At the tissue level, the vertical bands may represent foci of photoreceptor necrosis with surrounding intraretinal edema.18 After 1 week, the vertical bands had resolved partially with reduced hyperreflectivity within the outer nuclear layer. At 2 weeks, the different stages of laser burn formation were visible on biomicroscopy. Overlapping FD OCT may demonstrate the burns with outer highly reflective layer defects in high definition. Burns were poorly pigmented and either barely visible or invisible, without significant RPE reactivity after 2 weeks (Figure 4). There were localized areas of hyporeflectivity within outer highly reflective layer that corresponded to the

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burns. We observed all laser burns to remain highly localized, with no axial or lateral spread to adjacent RPE cells and photoreceptors.

treated sectors. In our study, we found a significant 26-␮m reduction in mean thickness within the treated ETDRS sector, and our FD OCT findings after treatment seem to be consistent with this previous work. As yet, there are no published data regarding thickness changes within the treated sector at 3 months after laser for DME. We found sustained and significant reductions in retinal thickness within the treated sector over the longer term. We may speculate that this reduction in ETDRS sector retinal thickness may correlate with the observed trends of improved visual acuity and clinical resolution of DME in this study. These laser parameters have remained relatively unchanged until the last decade, when the introduction of newer laser systems of different wavelengths have led to a reinvestigation of underlying mechanisms and therapeutic parameters for DME.6 –9 A better understanding of the laser-induced tissue effects within the outer retina has led to laser technology being developed to target the RPE and to minimize outer retinal injury.6,20 Currently, the system of micropulse diode laser uses subthreshold parameters that apparently maximize the thermal localization of the laser burn within the RPE.21 Good results with this technique have been reported.7,8 However, there have been few studies that have examined the in vivo morphologic effects of barely visible, shorterduration laser in DME.22 The modified ETDRS technique has recommended barely visible (light gray, threshold) burn intensity for conventional laser macular photocoagulation. Spot size has been reduced to 50 ␮m, with 50- to 100-millisecond pulse durations for both focal and full grid laser (2 burn width spot spacing, 100 ␮m) treatments. We used the Pascal system for macular photocoagulation, and this allows controlled application of arrays with predetermined parameters. After a laser application, the complete array of spots may not be visible clinically. We routinely imaged macula zones treated with this technique using FD OCT and AF to assess the extent of the treated area, thus avoiding unnecessary retreatment. In the immediate term, the laser burns were confirmed by FD OCT and AF imaging in all patients. None of the eyes required higherfluence laser retreatments in the immediate term. We published AF and FD OCT imaging data that suggested lower intensity and reduced fluence burns could achieve effective uptake within outer retina.18 This study confirmed effective laser uptake using the Pascal multispot technique at 10- to 20-millisecond pulse durations. Furthermore, our analysis of barely visible laser titration burns on FD OCT showed effective uptake at the level of the outer retina, and positive clinical results have been published previously in Manchester for Pascal laser.11 In a recent audit of 313 Pascal laser cases, 118 macular laser cases were analyzed for 10- to 20-millisecond pulse durations (unpublished data). We found 62% of macular grid patients and 89% of macular focal laser patients had

● RETINAL THICKNESS WITHIN TREATED SECTOR:

On average, a mean of 5.6 ETDRS sectors were treated in each eye (range, 2 to 8 sectors). The mean retinal thickness for all 56 treated sectors (10 eyes) at baseline was 309 ␮m (standard deviation, ⫾ 23 ␮m). There was a significant reduction at 2 weeks (283 ⫾ 32 ␮m; P ⫽ .012), and then an increase to 303 ␮m (⫾ 16 ␮m) at 4 weeks. At 3 months after laser treatment, the mean retinal thickness in treated sectors had reduced to 289 ␮m (standard deviation, ⫾ 21 ␮m). This reduction in retinal thickness within the treated sector was found to be statistically significant compared with baseline (P ⫽ .02). ● RETINAL THICKNESS WITHIN CENTRAL SUBFIELD:

The mean CRT ⫾ standard deviation was 286 ⫾ 39 ␮m at baseline. A 5-␮m reduction in CRT was seen at 2 weeks (280 ⫾ 39 ␮m; P ⫽ .29) and 4 weeks (280 ⫾ 40 ␮m; P ⫽ .28). At 3 months after treatment, the average CRT was 288 ⫾ 45 ␮m, with no significant change observed compared with baseline (P ⫽ .82). ● CLINICAL OUTCOMES:

Five eyes underwent focal macula, 3 eyes had a full-grid laser, and 2 eyes had horseshoeshaped grid laser (Table). There was complete resolution of retinal edema on biomicroscopy in 8 of 10 eyes at 3 months, designated as positive clinical regression of DME by 2 experienced retina specialists (L.B.Y., P.E.S.). Two eyes required a repeat treatment with full grid laser after 4 months. The mean best-corrected Snellen visual acuities at baseline and 3 months after laser were 6/12.7 ⫾ 7.6 and 6/9.4 ⫾ 4.0, respectively. The change in vision was equivalent to a single Snellen line of improvement; however, this was not statistically significant at final follow-up compared with baseline (P ⫽ .08).

DISCUSSION IN THIS GROUP OF PATIENTS, WE DESCRIBE THE MORPHO-

logic features of barely visible 10-millisecond laser burns using FD OCT and AF techniques. The 10-millisecond pulse duration burns have a characteristic pattern of AF that diminishes with time.18 Further reductions in AF characteristics are likely to occur with localized photoreceptor apoptosis and RPE cell death. The observed laserinduced tissue alterations of barely visible 10-millisecond laser treatment have a similar natural history to threshold 10-millisecond Pascal laser burns reported previously.18 Recent work by Sandhu and associates investigated shortterm effects of conventional pulse duration argon laser in DME using time-domain OCT.19 At 2 weeks, they reported a significant 15.6-␮m reduction in retinal thickness within 984

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successful outcomes 5 to 6 months after laser treatment. There were no reported complications for any case. Based on modified ETDRS macular laser recommendations, our published findings, and favorable clinical audit outcomes, we may routinely use a lower-intensity laser power in patients to achieve clinical efficacy. Patients who require Pascal 10-millisecond laser often undergo AF and FD OCT evaluation after laser treatment at 1 hour to check laser burn coverage at the macula and to assess whether immediate laser retreatment is required. Patients also may be reviewed at 1, 2, and at 4 weeks to exclude any worsening of the macular edema when using lower energy levels and for consideration of additional laser retreatments. These investigations are undertaken as part of routine laser management for the patient. AF and FD OCT immediately after treatment (routinely at 1 hour) is a valuable tool for assessing laser burn coverage and is helpful for targeting further laser treatment and for preventing overlapping burns, especially in complex cases where multiple laser treatments have been performed previously. The moderate reflectivity alterations within the outer nuclear and outer plexiform layers, together with complete sparing of inner retina, may suggest reduced light scattering within the retina resulting from the laser and may explain the reduced visibility of burns. Framme and associates described the tissue reactions of conventional retina laser lesions using spectral-domain OCT.23 A neodymium:yttrium–aluminum– garnet laser was used to generate grey-white visible, 100millisecond conventional burns that produced full-thickness hyper-reflectivity changes on OCT at 1 hour after laser treatment. In the long term, RPE atrophy subsequently developed from the higher-fluence, visible conventional laser burns used by Framme and associates. AF may track the microglial–lipofuscin effects over time, and the autofluorescent signal changes at 3 months did not show signs of expansion. In our group of patients, we observed 10-millisecond barely visible burns to remain highly localized to the junction between the inner segment and outer segment of the photoreceptors, with no axial or lateral spread within outer retina. We have demonstrated clear spatial localization of barely visible burns at all time points. In the presence of exudative, cystoid, and sponge-like DMO, we consistently were able to locate the burns with AF. The clinical outcomes of barely visible 10-millisecond laser treatment in our cohort of patients are difficult to

analyze in view of small numbers and lack of controls. However, we observed a significant reduction in mean retinal thickness within the treated sector between baseline and 3 months after laser treatment. However, the most reliable OCT parameter to quantify laser efficacy remains unclear. It is widely recognized that CRT remains the benchmark parameter for aiding the biomicroscopic diagnosis of ETDRS clinically significant macular edema. Recent evidence suggests that different OCT systems may produce variable and different macular thickness values in the same patient when obtained simultaneously.24 This may be because of differences in normative databases used to quantify normal ranges of values for each of the 9 ETDRS sectors using different OCT systems. We have shown how retinal thickness changes within the treated sector may be a sensitive index of effect for monitoring responses to barely visible laser, in addition to CRT values. The introduction of FD imaging has allowed us to attempt to visualize the outer retina changes associated with 10millisecond macular laser photocoagulation. The vertical bands of moderate reflectivity observed on FD OCT may consist of necrotic photoreceptor elements and focal edema within the outer plexiform layer.18 After 2 to 4 weeks, the edema had resolved to leave hyporeflective defects within the outer highly reflective layer that corresponded to partially pigmented or nonpigmented laser lesions. Increased reflectivity alterations within the junction between the inner segment and outer segment of the photoreceptors and apical RPE may indicate photoreceptor proliferation to sites of necrotic photoreceptors.25 The adjacent highly reflective layer was unaffected on either side of the burns, with barely visible fibrous scar formation on biomicroscopy. The technique of barely visible Pascal macular photocoagulation may produce highly localized retinal lesions and effective treatment outcomes for patients with DME. FD OCT in combination with AF may be useful 1 hour after laser treatment to confirm laser burn application while showing the extent of the treated area. AF thereafter may be used as a monitoring tool for barely visible treatments, either to confirm successful placement of burns or to plan retreatments for recurrent, persistent DME. Barely visible 10-millisecond Pascal macular laser photocoagulation may induce less tissue damage than conventional threshold laser photocoagulation while retaining therapeutic properties.

SUPPORTED BY THE MANCHESTER ACADEMIC HEALTH SCIENCES CENTER (MAHSC), THE NIHR MANCHESTER BIOMEDICAL Research Center, University of Manchester, United Kingdom, and Optimedica Corporation, Santa Barbara, California. Dr Marcellino is an employee of Optimedica Corporation. Dr Stanga has received financial support from Optimedica Corporation. Involved in design and hypothesis of study (M.M.K.M., P.E.S.); Data acquisition (M.M.K.M., J.C.B.G., D.B.H., L.B.Y., N.P., S.J.C., G.S.T., P.E.S.); Data analysis and interpretation (M.M.K.M., J.C.B.G., G.R.M., D.B.H., L.B.Y., N.P., S.J.C., G.S.T., P.E.S.); Patient recruitment and data acquisition (M.M.K.M., R.M., D.B.H., L.B.Y., N.P., S.J.C., G.S.T., P.E.S.); Statistical expertise (M.M.K.M., D.B.H., G.R.M., P.E.S.); Drafting of the manuscript (M.M.K.M., J.C.B.G., G.R.M., D.B.H., L.B.Y., N.P., S.J.C., G.S.T., P.E.S.); and Critical revision of the manuscript (M.M.K.M., J.C.B.G., G.R.M., D.B.H., L.B.Y., N.P., S.J.C., G.S.T., P.E.S.). The institutional review board (Greater Manchester Central Research Ethics Committee) reviewed this retrospective cohort study, and no ethical approval was required. The study adhered to the tenets of the Declaration of Helsinki.

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13. Leitgeb R, Hitzenberger CK, Fercher AF. Performance of Fourier domain vs. time domain optical coherence tomography. Opt Express 2003;11:889 – 894. 14. Costa RA, Skaf M, Melo LA Jr, et al. Retinal assessment using optical coherence tomography. Prog Retin Eye Res 2006;25:325–353. 15. Stanga PE, Kychenthal A, Fitzke FW, et al. Retinal pigment epithelium translocation after choroidal neovascular membrane removal in age-related macular degeneration. Ophthalmology 2002;109:1492–1498. 16. Chauhan DS, Marshall J. The interpretation of optical coherence images of the retina. Invest Ophthalmol Vis Sci 1999;40:2332–2342. 17. Otani T, Kishi S, Maruyama Y. Patterns of diabetic macular edema with optical coherence tomography. Am J Ophthalmol 1999;127:688 – 693. 18. Muqit MMK, Gray JCB, Marcellino GR, et al. Fundus autofluorescence and Fourier-domain optical coherence tomography imaging of 10 and 20 millisecond Pascal retinal photocoagulation treatment. Br J Ophthalmol 2008;2008;93: 518 –525. 19. Sandhu SS, Birch MK, Griffiths PG, Talks SJ. Short-term effects of focal argon laser treatment in diabetic maculopathy as demonstrated by optical coherence tomography Retina 2007;27:13–20. 20. Mainster MA. Wavelength selection in macular photocoagulation. Ophthalmology 1986;93:952–958. 21. Stanga PE, Reck AC, Hamilton AM. Micropulse laser in the treatment of diabetic macular oedema. Semin Ophthalmol 1999;14:210 –213. 22. Framme C, Brinkmann R, Birngruber R, et al. Autofluorescence after selective RPE laser treatment in macular diseases and clinical outcome: a pilot study. Br J Ophthalmol 2002; 86:1099 –1106. 23. Framme C, Walter A, Prahs P, et al. Structural changes of the retina after conventional laser photocoagulation and selective retina treatment (SRT) in spectral domain OCT. Curr Eye Res 2009;34:568 –579. 24. Leung CK, Cheung CY, Weinreb RN, et al. Comparison of macular thickness measurements between time domain and spectral domain optical coherence tomography. Invest Ophthalmol Vis Sci 2008;49:4893– 4897. 25. Paulus YM, Jain A, Gariano RF, et al. Healing of retinal photocoagulation lesions. Invest Ophthalmol Vis Sci 2008; 49:5540 –5545.

REFERENCES 1. Early Treatment Diabetic Retinopathy Study Research Group. Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Arch Ophthalmol 1985;103:1796 –1806. 2. Schatz H, Madeira D, McDonald HR, et al. Progressive enlargement of laser scars following grid laser photocoagulation for diffuse diabetic macular edema. Arch Ophthalmol 1991;109:1549 –1551. 3. Hudson C, Flanagan JG, Turner GS, et al. Influence of laser photocoagulation for clinically significant macular oedema (DMO) on short-wavelength and conventional automated perimetry. Diabetologica 1998;41:1283–1292. 4. Bandello F, Polito A, Borrello MD, et al. “Light” versus “classic” laser treatment for clinically significant diabetic macular oedema. Br J Ophthalmol 2005;89:864 – 870. 5. Writing Committee for the Diabetic Retinopathy Clinical Research Network, Fong DS, Strauber SF, et al. Comparison of the modified early treatment diabetic retinopathy study and mild macular grid laser photocoagulation strategies for diabetic macular edema. Arch Ophthalmol 2007;125:469 – 480. 6. Framme C, Schuele G, Roider J, et al. Influence of pulse duration and pulse number in selective RPE laser treatment. Lasers Surg Med 2004;34:206 –215. 7. Luttrul JK, Musch DC, Mainster MA. Subthreshold diode micropulse photocoagulation for the treatment of clinically significant macular oedema. Br J Ophthalmol 2005; 89:74 – 80. 8. Moorman CM, Hamilton AM. Clinical applications of the Micropulse diode laser Eye 1999;13:145–150. 9. Blumenkranz MS, Yellachich D, Anderson DE, et al. New Instrument: semiautomated patterned scanning laser for retinal photocoagulation. Retina 2006;26:370 –375. 10. Jain A, Blumenkranz MS, Paulus Y, et al. Effect of pulse duration on size and character of the lesion in retinal photocoagulation. Arch Ophthalmol 2008;126:78 – 85. 11. Sanghvi C, McLauchlan R, Delgado C, et al. Initial experience with the Pascal photocoagulator: a pilot study of 75 procedures. Br J Ophthalmol 2008;92:1061–1064. 12. Schmitz-Valckenberg S, Holz FG, Bird AC, Spaide RF. Fundus autofluorescence imaging: review and perspectives. Retina 2008;28:385– 409.

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Biosketch Mahiul MK. Muqit, BSc, MBChB, MRCOphth, received his medical degree from the University of Glasgow and bachelors degree from St Mary’s Hospital Medical School, University of London. He is a Specialist Registrar in Ophthalmology, and Clinical Research Fellow at Manchester Royal Eye Hospital. Mr Muqit is currently in full-time research on a PhD programme in the School of Medicine at the University of Manchester. His clinical and research interests include diabetic eye disease, laser photocoagulation, ocular imaging techniques, and vitreoretinal surgery.

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Biosketch Paulo E. Stanga, MD, is a Consultant Ophthalmologist and Vitreoretinal Surgeon for the Manchester Royal Eye Hospital, Associate Professor in Ophthalmology for the University of Manchester and member of staff of the Manchester Biomedical Research Centre. Mr Stanga has set up a Retina Research Fellowship Program and his current research interests are new therapies for diabetic retinopathy, macular oedema and age-related macular degeneration, laser-tissue interaction and electronic retinal implants for artificial vision.

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