Theories on the mechanism of action of PRP have expanded and may not be mutually exclusive. During the process of DRS, the researchers came to an agreement on the value of peripheral scatter treatment as a means in which to ablate ischemic retina presumably to decrease the stimulus for neovascular growth.68 Since then, vascular endothelial growth factor (VEGF) has been identified as playing a major role in the development of PDR.76 PRP laser appears to decrease VEGF production and induces the release of angiostatin, a potent inhibitor

of neovascularization in the retina and vitr- eous.77–79 A great number of other agents are

undoubtedly involved and there appears to be an alteration in the complex balance and interaction of growth factors (e.g., angiopoietin,80,81 cortistatin,82 insulin-like growth factor-1,83 basic fibroblast growth factor,4 platelet-derived growth factor,4 endothelin-1,84 transforming growth factor beta- 1,85 connective tissue growth factor,86 growth hormone87) and inhibitors (e.g., pigment epithe- lium-derived factor,88–90 soluble vascular endothelial growth factor receptor-1,91 somatostatin,4 endostatin,92 angiostatin,79 thrombospondin4) that result in tissue proliferation in PDR.4,93

Panretinal photocoagulation may also allow an influx of oxygen from the choroid into the ischemic retina by thinning the retina and focally diminishing oxygen consumption by outer retinal mitochondria.94 The oxygen tension in the preretinal vitreous cavity is greater over areas of retina treated by PRP than over untreated areas in diabetic eyes.95 Consequently, there is a reduction of blood flow in major retinal vessels and decreased venous dilatation fol-

lowing peripheral scatter laser photocoagulation for PDR.96,97

The physical effect of retinal photocoagulation is a result of the absorption of light energy not only by pigment, primarily melanin in the retinal pigment epithelium, but also by hemoglobin. Light energy is thereby transformed into heat energy, which is conducted into the neurosensory retina. The amount of laser energy required to achieve the desired degree of photocoagulation is dependent on the concentration of laser energy delivered to the retina through the media of the eye. Retinal whitening becomes visible as the retina coagulates and the intensity of the whitening relates to the depth of heat penetration into the retina. Very intense whitening of the

retina indicates full thickness retinal photocoagulation, regardless of the laser wavelength used.75,98

9.2.1 Indications

The current indications for laser treatment of PDR are based on the recommendations from the prospective, randomized, controlled trials carried out by the Diabetic Retinopathy Study group and the Early Treatment Diabetic Retinopathy Study group. The DRS identified the clinical features of eyes with proliferative diabetic retinopathy at high risk for visual loss and termed this group as highrisk proliferative diabetic retinopathy (HR-PDR), which included eye with either (1) neovascularization of the disk (NVD) equal to or greater than standard photograph 10A or (2) preretinal or vitr-

eous hemorrhage associated with NVD < standard photograph 10A or NVE 1/2 disk area.65,66,99

Figure 9.1 shows standard photograph 10A. The risk of severe visual loss in eyes with HR-PDR was shown to be reduced by greater than 50% over a

Fig. 9.1 ETDRS standard photo 10A. NVD (NV on or within one disk diameter of the disk border) of approximately one-quarter to one-third disk area67 (reproduced with permission from the Early Treatment Diabetic Retinopathy Study Research Group. All rights reserved)

2-year period with the application of peripheral scatter laser photocoagulation, now commonly

referred to as panretinal photocoagulation (PRP).65,99 Despite clear benefit from PRP, the

4-year rate of severe visual loss (visual acuity less than 5/200, measured at two or more consecutive visits) in eyes with high-risk PDR was 20.4%.67 It is important to note that the DRS included cases with HR-PDR of varying degrees of severity, not just new-onset HR-PDR.

The ETDRS was designed to compare the effect of early vs. delayed PRP in earlier stages of diabetic retinopathy in an effort to further decrease the risk of visual loss. The 5-year rate of severe visual loss in the ETDRS was 2.6 and 3.7% in the early treatment and delayed deferral group, respectively.67 The ETDRS adopted from the DRS the definition of severe nonproliferative diabetic retinopathy (S-NPDR) and highrisk proliferative diabetic retinopathy and expanded the diabetic retinopathy severity scale.67,100

Regarding the treatment of mild-to-moderate NPDR, the ETDRS recommended against PRP as the risk of severe visual loss in this group was low and there was adverse risk of moderate visual loss following treatment. This recommendation was made with the provision that these patients could be followed for progression.67

The ETDRS recommendations for the treatment of severe nonproliferative diabetic retinopathy (S-NPDR) and early proliferative diabetic retinopathy (E-PDR) with scatter laser (PRP) were less definite.67 The ETDRS definition of S-NPDR in Table 9.4 refers to ETDRS photographic fields

(Fig. 9.2), to standard photo 2A (Fig. 9.3), and to standard photo 8A (Fig. 9.4). Early PDR was defined as new vessels present, but less than highrisk PDR. The ETDRS made a recommendation to ‘‘consider’’ PRP in eyes with severe nonproliferative diabetic retinopathy and early proliferative

Fig. 9.2 ETDRS diagram for right eye showing 308 photographic fields. Fields 4–7 are used for grading severe nonproliferative diabetic retinopathy (the ETDRS diagram was reproduced with permission from Ophthalmology.628 Copyright # 1991 American Academy of Ophthalmology. All rights reserved)

Table 9.4 ETDRS definition of severe nonproliferative diabetic retinopathy

Either of two definitions below

1.Any three of the following findings

a.Soft exudates in at least two fieldsa

b.Venous beading in at least two fieldsa

c.Intraretinal microvascular abnormalities in at least two fieldsa

d.Hemorrhages and microaneurysms standard photo 2A Present in at least one fielda

2.Intraretinal microvascular abnormalities (IRMA) in all four fieldsa and IRMA severity standard photo 8A in at least two fieldsa

a308 photographic fields 4–7 (shown in Fig. 9.2) Standard photograph 2A is shown in Fig. 9.3 Standard photograph 8A is shown in Fig. 9.4

Fig. 9.3 ETDRS standard photograph 2A demonstrating moderate hemorrhages and microaneurysms (reproduced with permission from the Early Treatment Diabetic Retinopathy Study Research Group. All rights reserved)

Fig. 9.4 ETDRS standard photograph 8A demonstrating IRMA severity (reproduced with permission from the Early Treatment Diabetic Retinopathy Study Research Group. All rights reserved)

diabetic retinopathy.67 This cautious wording may have led physicians away from treating this group of eyes. There are, however, some issues that may compel a decision to treat. For example, the ETDRS used somewhat stronger wording in favor of treating at least one eye when both eyes are approaching HR-PDR by stating that it ‘‘seems particularly appropriate.’’ They logically considered the potential difficulty in urgently treating both eyes if they simultaneously developed HR-PDR at a later date. The 5-year risk of developing HR-PDR is greater than 70% in this cohort.67

There are other factors that might reasonably influence the clinician to offer PRP in eyes with S-NPDR or E-PDR. Such factors include situations in which an eye may be at increased risk of progression or poor outcome (Table 9.5).101 Patients who are unable to adhere to appropriate follow-up examinations are at increased risk of progressing to HR-PDR without being detected and treated in a timely fashion.67 In ETDRS report #17, there was a higher risk to progress to vitrectomy in eyes of patients with type 1 diabetes mellitus with poor metabolic control.69 In addition, the ETDRS and DRVS described a disproportionate percentage of patients with type 1 diabetes mellitus with very severe PDR consistent with other studies suggesting this group of eyes is at increased risk of

Table 9.5 Proposed factors promoting decision to treat S-NPDR and E-PDR

1.Bilateral diabetic retinopathy approaching high-risk PDR

2.Poor compliance with follow-up visits

3.Poor metabolic control

4.Type 1 diabetes mellitus (especially, if poorly controlled)

5.Presence of diabetic macular edema

6.Presence of iris neovascularization

7.Pregnancy

8.Recent, rapid improvement in metabolic control

9.Previous severe visual loss in fellow eye from PDR

10.Total NVE area greater than two disk areas

progression.70,102 Eyes with diabetic macular edema are at increased risk of both severe visual loss and vitrectomy and these eyes might be treated with PRP after appropriate management of edema.67 Findings of neovascularization of the

iris (NVI) or neovascular glaucoma (NVG) portend a poor prognosis.67,103 Such eyes may not

present with high-risk PDR, especially if there is a posterior vitreous detachment.38,39 Patients with recent improvement in diabetes management with a rapid decrease in hemoglobin A1c may experience an ‘‘early worsening’’ in retinopathy before long-term stabilization.8 Therefore, documented progression to S-NPDR or E-PDR in this situation may be an indication for PRP. Similarly, worsen-

ing of diabetic retinopathy is well described in pregnancy.104–106 Other factors in favor or treat-

ment include the previous severe loss of vision from diabetic retinopathy in the fellow eye and, possibly, family history of poor outcome from diabetic retinopathy.107 In the ETDRS there were few eyes with NVE greater than two disk areas in extent to provide significant data.67 These eyes with more extensive NVE might be reasonably considered for PRP as they appear to be at increased risk of severe visual loss.70

Alternatively, there are factors that may influence the physician to observe S-NPDR and E-PDR. For example, observation may be preferable in cases with laser-induced complications in the fellow eye, patient preference after counseling, good metabolic control, no DME, asymptomatic eye, low-risk fellow eye, and in cases without documentation of progression (e.g., the initial visit).

Fig. 9.5 Elevated iris pupillary vascular tuft (microhemangioma) demonstrated by slitlamp photograph (a). The Iris fluorescein angiogram reveals numerous hyperfluorescent

vascular tufts at pupillary margin (b) (reprinted with permission from Bakke et al.114 Copyright #2006 Wiley-

Blackwell. All rights reserved)

A unique subset of patients may present with ‘‘end-stage’’ or ‘‘burned-out’’ proliferative diabetic retinopathy (Fig. 9.6). These eyes may have extensive fibrous proliferation with or without traction retinal detachment (TRD) in the absence of a sig-

nificant vascular component to the preretinal tissue.117,118 In these cases the neovascularization has

undergone spontaneous involution. Therefore, the value of PRP is debatable. As vitreous traction may continue in the absence of active NV, PRP may be helpful in creating chorioretinal adhesions

to decrease the likelihood of progressive TRD.20,24–26,34,119,120 However, there may be con-

cern that inflammation associated with PRP may stimulate fibrous tissue contraction. This issue has not been studied adequately for definitive recommendations.

9.2.2 PRP Technique

The application of panretinal photocoagulation continues to evolve in an effort to maximize the benefits and minimize the risks of treatment. The ETDRS technique of applying scatter laser in PDR was proven effective.67,68 The following is a detailed review of this technique and a discussion of considerations for modification based on new information and technology.

Prior to initiating PRP, consideration is given to pain management in order to ensure patient satisfaction and continuity of care. Peribulbar and retro-

bulbar anesthesia are equally effective for pain control and were used optionally in the ETDRS.68,121

There appears to be little benefit of oral medications (benzodiazepines, acetaminophen, nonsteroidal

careful approach is necessary in eyes with pale fundi. Although greater laser energy may be required due to decreased concentration of melanin, these eyes provide less contrast in which to appreciate laser-induced whitening.151 Thus, a relatively less intense burn may be a suitable goal. Intense laser treatment causes more prominent visual field defects than mild-to-moderate whitening.152

Supported by preliminary studies, less intense burns are often the current goal in an effort to

decrease pain with treatment and to reduce the side effects of PRP.128,129,131,152,153 The Diabetic

Retinopathy Clinical Research Network protocol called for mild-to-medium white burns.154 Pushing the limits of decreasing the laser-whitening effect on the retina, diode subthreshold micropulse laser employs short bursts of laser to produce subvisible laser applications limiting the conduction of heat from the retinal pigment epithelium to the retina in an effort to minimize side effects of treatment.155 Randomized controlled trials are needed to compare these strategies with ETDRS protocol.

To achieve a desired intensity the treating ophthalmologist may make adjustments in several laser parameters. The laser spot size and duration are first selected after which the power is adjusted to reach the desired goal of retinal whitening.68 The ETDRS protocol called for a setting of 500 mm for the diameter of the laser spot using a Goldmann lens. This setting was adjusted to 250–300 mm when using the Rodenstock lens to achieve a similar effect without changing the number of burns required for a complete initial treatment. However, calculations suggest that a photocoagulator spot size setting of 383 mm using a Rodenstock panfundoscopic lens might more closely approximate the retinal photo-

coagulative effect of a spot setting of 500 mm while using a Goldmann lens (Table 9.6).156–158 In the

ETDRS, allowance was made for adjusting to a smaller spot size to reach the desired intensity in eyes with opaque media (cataract or vitreous

hemorrhage).68 The spot size may also be reduced to allow for better pain control.128,132 When using

smaller spot sizes, a greater number of burns are needed to treat a comparable area of the retina. As the area of the laser spot is proportional to the square of the radius, four times as many spots may be needed if the spot size is reduced by 50%.

Another concern with the use of a smaller laser spot size is the risk of creating a hyperintense burn resulting in the rupture of Bruch’s membrane and hemorrhage.159

The laser flash duration in the ETDRS was 0.1 s, but longer duration was allowed if needed to reach the intensity goal as needed in eyes with opaque media.68 Alternatively, the flash duration may be shortened in an effort to decrease pain with treatment.128 Laser flashes with shorter duration

(0.01–0.05 s) are less painful than longer duration (0.1 s) controlling for end point laser intensity.131,132

Flash duration also correlates with breadth and depth of the zone of coagulation. Longer pulse duration is associated with greater conductive spread of retinal photocoagulation, likely accounting for pain and possibly accounting for therapeutic benefit.132 Burns longer than 0.1 s duration may increase the risk of traction retinal detachment following treatment for PDR.160 Shorter pulse dura-

tion is associated with increased risk of chorioretinal hemorrhage.161,162 This risk may be mitigated

by increasing the laser spot size.161

The goal of spacing of laser burns in the retina in the ETDRS was to aim for a final appearance of burn separation (after expansion of the burn) of one-half burn diameter. Therefore, laser burns could be placed from one-half to one burn diameter apart to reach this target (Fig. 9.7).68 As laser scars may expand over time, this pattern may result in

confluent atrophy from laser with attendant loss of visual field (Fig. 9.8).163,164 Although this adverse

effect may call for a change in the pattern density of

Fig. 9.7 Immediate post-laser appearance of retina following ETDRS-style PRP

Table 9.6 Comparison of fundus contact lenses for PRP laser

Number of burns = ETDRS PRPa with laser settings as shownbelow:

a1600 burns using 500 mm laser setting with a Goldmann contact lens (assuming fixed pulse duration)

Retinopathy Diabetic Proliferative of Treatment 9

239

PRP, the ETDRS showed that the beneficial effects of full scatter laser as described above was superior to mild scatter (less dense pattern) laser in the treatment of PDR.67 The Diabetic Retinopathy Clinical Research Network modified the laser pattern density from that used by the Early Treatment Diabetic Retinopathy Study by spacing burns one burn

diameter apart without aiming for a final burn separation of one-half burn diameter after expansion (Fig. 9.9).154

The location within the retina for the placement of scatter laser was also well defined in the ETDRS. The posterior extent of scatter laser was described as forming an oval around the macula and including the disk ‘‘defined by a line passing two disk diameters above, temporal to, and below the center of the macula and 500 mm from the nasal one-half of the disk margin.’’ The anterior extent of scatter laser reaches ‘‘to or beyond the equator’’ avoiding direct treatment of major vessels, preretinal hemorrhage, and chorioretinal scars (to avoid rupturing Bruch’s

membrane).68 Since the ETDRS publications, several studies emphasize the importance of treating the retina well anterior to the equator, especially in severe cases, to reduce the risk of anterior neovascularization and associated complications.166–169 Recent insights also suggest the utility of applying laser in a pattern on each side of the medium-sized, radiating, midperipheral retinal vessels as the hypoxic retinal tissue mantle in this paravascular area appears to a persistent source of neovascular cytokines.18

With some exceptions the ETDRS required direct, confluent treatment (200–1000 mm, 0.1–0.5 s, moderately intense whitening) of small, flat areas of NVE (not more than 2 disk areas, i.e., circle of 1.5 disk diameter) avoiding treatment closer than 500–1000 mm from the center of the macula. The base of elevated NVE was treated confluently as well. Although direct photocoagulation may be currently less popular for the purpose of regression of NV, there may be a role for treating NVE to create an adhesion in order to reduce the risk of retinal detachment from future vitreous/membrane contraction.119,174 Photocoagulation for PDR rarely involves the macula with the notable exception of treating ischemic areas temporal to the center of the macula in cases of active PDR despite standard PRP.67 In addition, avoiding direct treatment over the long posterior ciliary nerve minimizes pain and reduces the risk of parasympathetic denervation of iris and ciliary body.175

As PRP is frequently completed in two or more sessions, a decision is made as to which areas of the retina need treatment first. The order of treatment in the ETDRS was optional for the ophthalmologist. Then as now, the most urgent areas of the retina were treated first. If vitreous hemorrhage

threatens to gravitate inferiorly, treatment is begun in the inferior quadrants. If macular edema is present, the nasal quadrants are treated first in order to minimize adverse effects on visual acuity. When treating the temporal quadrants, initial treatment beginning posteriorly around the macula may help lessen the chance of inadvertent macular photocoagulation.68

Treatment anterior to the equator was optional

in the ETDRS, but there are compelling reasons to routinely treat well anterior to the equator.17,171

Standard panretinal photocoagulation applied posterior to the equator may cause severe visual field loss rendering the patient unable to drive an automobile.164 A prospective randomized trial showed that anterior PRP is as effective as standard PRP in causing involution of PDR with fewer complications of DME and less visual field loss.176 In addition, anterior PRP reduces the risk for anterior hyaloidal neovascularization and retinal detach-

ment following subsequent vitrectomy sur- gery.18,119,166–168,174 Figure 9.10 shows an example

of neovascular proliferation on the anterior border of PRP. The potential for anterior choroidal effusion with shallowing of anterior chamber following PRP anterior to the equator may be minimized by

avoiding excessive laser intensity and by dividing the treatment into multiple sessions, especially in hyperopic eyes.177

The ETDRS protocol specified the details regarding the duration of a laser session, the number of sessions, the time between sessions, and the definition of completion of PRP. The number of laser burns per session did not exceed 900 in order to avoid complications from excessive treatment.68 However, when urgent treatment completion is needed, exceeding this guideline is not proscribed in clinical practice.178 Alternatively, fewer laser burns per session may be considered in a sensitive patient or when shallow anterior chamber angles threaten closure.67

The number of sessions to complete initial PRP was two or more in the ETDRS.68 A randomized controlled trial showed that PRP may be completed in a single treatment without increased long-term adverse effects compared with divided sessions. Short-term side-effects did include serous choroidal and retinal detachment and angle closure.178 Another more recent prospective trial by the DRCR.net demonstrated no major increased risk of macular edema in comparing single-session vs. four-session PRP in eyes with severe NPDR or early PDR without pretreatment diabetic macular edema.154 Thus, there is latitude in deciding the number of sessions in which to complete PRP.

In the ETDRS, the time interval between treatment sessions was at least 2 weeks apart if total of two sessions were planned for completion of treatment. A separation of at least 4 days was required if three or more episodes were planned for complete initial PRP. Completion of initial PRP occurred within 5 weeks in the ETDRS.68 A desire for rapid completion of initial PRP is considered in eyes with PDR at high

risk for vitreous hemorrhage.68 An increased interval between laser sessions is desirable in eyes with diabetic

macular edema, especially if adjunctive therapy is not employed as described later in this chapter.178,179

The ETDRS protocol defined the completion of PRP in terms of total laser applications from all initial treatment sessions. Between 1200 and 1600 laser burns were required for initial PRP to be complete.68 However, there may be situations in which less extensive laser may be satisfactory. For example, response to PRP can be rapid with dramatic resolution of NV within 3 weeks and these early responders tend to remain stable for at least 6 months.180 As adverse effects from laser are directly related to number of laser burns, a predetermined number of burns may be imprudent in cases where NV resolves before completion of intended PRP.67 An alternative strategy in this scenario may be to observe rather than continue treatment session after regression from high-risk PDR with reinstitution of treatment when worsening of NV is documented. Another factor to consider in deciding when to stop initial PRP is the status of the vitreous. PRP is known to precipitate posterior vitreous detachment, and if PVD were documented before completion of initial PRP, observation may be in order given

the anticipated benign clinical course reported in eyes with PVD.38,181,182 Alternatively, if vitrectomy

surgery is planned in an eye with severe PDR,

more extensive PRP appears to improve outcome.49,183,184 Thus, although guidelines are help-

ful, a predetermined number of laser applications may not be a clinically relevant goal in the treatment of proliferative diabetic retinopathy.

During follow-up after the completion of initial PRP, retreatment was optional in the ETDRS.