peeling or delamination required) and fewer com-

plications (retinal tears) with vitrectomy aided by autologous plasmin enzyme.281,282 Several pharma-

cological agents are under evaluation and are discussed later in this chapter. Interestingly, injection of SF6 has also been used to induce PVD to retard progression on PDR.283 Further studies are needed to better define the role of pharmacologic vitreolysis in the treatment of PDR.

9.4 Vitreoretinal Surgery

Vitreoretinal surgery has an established role in the

management of complications of diabetic retinopathy.69,71,72 Vitrectomy was required in 208 eyes

(5.6%) of 3711 patients enrolled in the ETDRS underscoring the lack of universal response of PDR to laser treatment.69 Prior to the Diabetic Retinopathy Vitrectomy Study (DRVS), vitrectomy was reserved for dense nonclearing vitreous hemorrhage greater than 1-year duration and for traction retinal detachment involving the center of the macula. These conservative indications reflected the lack of experience with vitrectomy and the high rate of serious complications at that time.71 Both the ETDRS and the DRVS were hindered by the lack of endophotocoagulation, which was not available until 1983.71 With gains in experience and technology, the role of vitrectomy has expanded significantly since these important studies were published.

9.4.1 Indications

Following vitreous hemorrhage and traction retinal detachment are other less pressing indications for vitrectomy such as dense premacular hemorrhage, fibrovascular proliferation, and diabetic macular edema as well as conditions not specific to diabetes including macular pucker, vitreomacular traction, and macular hole. More severe conditions that are now approached include combined rhegmatogen- ous–traction retinal detachment, neovascular glaucoma, uncontrolled hemolytic/ghost cell glaucoma, anterior hyaloidal fibrovascular proliferation, and

fibrinoid syndrome with retinal detachment.284–286 The following sections define indications with management considerations and outcomes among these subgroups.

Vitreous hemorrhage: Although vitreous hemorrhage is a common indication for vitrectomy, surgery may be avoided in most eyes. Observation alone may result in improvement.285 Bed rest with elevation of the head (with or without patching) may facilitate spontaneous resolution of vitreous hemorrhage.287–289 Intravitreal injection of hyaluronidase hastens the clearing of vitreous hemorrhage.278 When a portion of the retina can be visualized, panretinal photocoagulation is applied to induce regression of active neovascularization.285 Krypton laser and long-wavelength diode laser systems penetrate vitreous hemorrhage with greater facility than argon laser and indirect ophthalmoscopic delivery systems may be more effective than slitlamp delivery.285

The DRVS demonstrated the benefit of early vitrectomy (1–4 months from onset) in severe vitreous hemorrhage (<5/200 vision) resulting in earlier recovery of vision and better visual outcome at 2 and 4 years, especially in type 1 diabetes mellitus. There was no significant increased risk of the severe complication of NLP vision with early vitrectomy, though it occurred sooner in the early-surgery group compared with the deferral group.71 The DRVS enrolled 616 eyes with vision less than 5/200 due to severe vitreous hemorrhage with duration of less than 6 months. Eyes with VH present for at least 1 month were randomized to early vs. deferral of vitrectomy for 1 year. Recovery of vision of 20/100 or better by 3 months was more common in the early group (50%) compared with the deferral group (17%). The visual acuity at the 2-year follow-up was 20/40 or better in the early group was 25% compared with 15% in the deferral group (P ¼ 0.01). The benefit was even greater in patients with type 1 diabetes mellitus (36% early group vs. 12% deferral group, P ¼ 0.0001) compared with type 2 (16% early group vs. 18% deferral group). The benefit persisted at the 4-year follow-up visit and was most prominent in the type 1 patients, presumably due to the aggressive nature of PDR in these cases.71 In a survey of the American Society of Retinal Specialists in 2008, the vast majority of 366 respondents routinely performed vitrectomy

surgery between 1 and 3 months from onset of nonclearing vitreous hemorrhage.210

There are a number of issues to consider in evaluating the unimpressive results of early vitrectomy in type 2 patients. Poorer postoperative visual acuity may be a function of greater severity of maculopathy in type 2 patients compared with those with type 1 diabetes.71 In addition, the DRVS did not report an analysis of the vitreous status in these eyes.71 PVD is more common with age and is associated with better prognosis without intervention compared with eyes without PVD.38,182 Therefore, in clinical decision making, the use of preoperative B-scan examinations may be helpful in stratifying this group of eyes. Eyes with more extensive vitreoretinal attachments may benefit from vitrectomy to a greater degree than those with more complete PVD. Another influential factor in determining the timing of vitrectomy for vitreous hemorrhage is the presence and degree of activity of iris rubeosis. Prompt vitrectomy is indicated to clear the media for the application of PRP in cases of progressive rubeosis and neovascular glaucoma.285

Subsequent to the DRVS, a retrospective study reviewed 353 eyes operated for diabetic vitreous hemorrhage and reported improved vision in 81% of cases. Final vision of 20/200 or better was achieved in 48% of operated eyes and 5/200 or better in 79%.290 Favorable factors for good outcome were preoperative vision greater than 5/200, minimal cataract, no NVI/NVG, and PRP in at least one quadrant.184 These data and others argue in favor of preparing for vitrectomy with

augmentation of PRP laser when possible and applying endolaser at the time of surgery.69,285

Postoperative vitreous hemorrhage is common and usually clears with observation; however,

approximately 10% of cases require repeat vitrectomy or fluid–gas exchange.285,291 In a retrospec-

tive study of 484 consecutive vitrectomy procedures for various complications of PDR, 4% of eyes required repeat vitrectomy for vitreous hemorrhage.291

Ghost cell glaucoma: Glaucoma may be encountered as a consequence of diabetic vitreous hemorrhage as degenerated red blood cells obstruct trabecular outflow resulting in elevated intraocular pressure.292 This secondary open-

angle glaucoma occurs most commonly in aphakic and/or vitrectomized eyes, as ghost cells

do not penetrate the intact anterior hyaloid face.290,293–296 Ghost cells are erythroclastic red

blood cells that have become spherical, less pliable, and slower to clear from the eye. The indication for vitrectomy and anterior chamber lavage is uncontrolled intraocular pressure despite maximal medical therapy.297 Response to surgery is generally favorable.297

Dense premacular (subhyaloid) hemorrhage: In PDR with intact vitreous, dense premacular hemorrhage may be trapped between the internal limiting membrane and the posterior hyaloid face resulting in acute, profound loss of visual acuity. The thick red hemorrhage is well circumscribed, usually round or oval in shape, and obscures all view of the underlying retina (Fig. 9.12). The natural his-

tory is not well defined as these cases were grouped with vitreous hemorrhage in the DRVS.70,71 Most

subhyaloid hemorrhages will clear without vitrectomy by spontaneously breaking through into the vitreous cavity.284 However, dense nonclearing subhyaloid hemorrhages may be associated with fibrovascular proliferation, preretinal membrane formation, and traction macular detachment.298 Vitrectomy surgery is used in these eyes to speed

recovery of vision and decrease the risk of complications.290,298,299 Although it is desirable to allow a

few months time for the hemorrhage to clear, a further delay in surgery may make surgical dissection more difficult.285

Fig. 9.12 Dense premacular hemorrhage trapped between the partially separated posterior cortical vitreous and the retina

Traction retinal detachment: Vitreoretinal traction is common in PDR as neovascular membranes grow

within the cortical vitreous gel, create firm vitreoretinal adhesions, and contract over time.28,285 Break-

down of the blood–ocular barrier contributes to vitreous contraction and subsequent traction retinal detachment (Fig. 9.13).311 Traction macular

detachment acutely involving or threatening the macula has become the most common indication for vitrectomy since the ETDRS and DRS.285

The DRVS described the course of extramacular traction retinal detachment (TRD) in the posterior pole over a 2-year period.70 The study enrolled 290 eyes with vision 20/100 (or 20/400 due to

vitreous hemorrhage). At baseline the TRD measured at least four disk areas and extended within 308 from the center of the macula. Also included were TRD’s less than four disk areas if the vitreoretinal adhesions causing the elevation were within 308 from the center of the macula and were associated with either active new vessels or recent vitreous hemorrhage. Photocoagulation was permitted at the discretion of the ophthalmologist. Two or more lines of vision were lost in 43% of eyes from baseline to the 2-year examination. Severe visual loss (<5/200 at two consecutive 4-month visits) increased from 0% at baseline to 15% at 1 year and 24% at 2 years. Subgroup analysis revealed poor prognosis in eyes with active NV (defined as NV containing visible blood) or recent vitreous hemorrhage (defined as red in color). Severe visual loss in eyes with and without these characteristics was 21–30% and 14%, respectively. Among eyes with active NV or recent vitreous hemorrhage, the extent of TRD was also a significant factor for severe visual loss: 21% for eyes with TRD less than four disk areas compared to 30% for eyes with TRD greater than four disk areas. The most common causes of severe visual loss included vitreous hemorrhage and retinal detachment. Of significance, only 35.2% of all eyes with TRD had PRP at the baseline examination. By the 2-year follow-up examination, 54.8% had not received PRP.70 Cur-

rently, earlier intervention with PRP and vitrectomy offers an improved prognosis in these cases.70,285

The management of extramacular traction retinal detachments appears to be undergoing change. Traditionally, extramacular traction detachments were observed as the rate of progression into the macula (approximately 15% annual risk) was felt to be lower than the risk poor outcome with vitrectomy.312 However, the anatomic results following vitrectomy have improved since earlier reports and

the risk of loss of vision with vitrectomy has decreased.274,313,314 Unfortunately, the functional

results of vitrectomy surgery following the successful repair of macula-off traction retinal detachment remains disappointing (Table 9.7). Consequently, a number of researchers have called for vitrectomy

surgery at an earlier stage, prior to severe visual loss from TRD.274,315

A number of retrospective studies of eyes operated for diabetic TRD are available for review,

although direct comparison is not possible due to variability in the patient populations (Table 9.7). A variety of surgical techniques have been employed. Improving anatomic results have been apparent with the evolution of vitrectomy from removal of axial traction by core vitrectomy to sophisticated methods of relieving tangential traction by segmentation and delamination with membrane peeling

relegated to a minor role in the management of minimally adherent membranes.49,274,313,315–319

Reports over the past 20 years indicate visual

improvement may be achieved in 60–75% of cases.274,313,320–323 The final visual acuity results

generally reveal a modest 20/200 or better in

47–57% of eyes, and 5/200 or better in

69–77%.313,318,319,321,322,324,325 Successful anatomic

reattachment of the macula is achieved in 81–100%

of cases.313,318,319,321,322,324,325 Favorable factors

include age <50 years, preoperative PRP laser, preoperative vision >5/200, minimal cataract/vitreous hemorrhage, no NVI/NVG, less extensive retinal neovascularization, absence of iris neovascularization, macular detachment for less than 30 days, no

need for lensectomy/gas tamponade, and no iatrogenic break.49,69,325,326 The incidence of surgical

complications appears to be greater in eyes undergoing vitrectomy for PDR with TRD compared with other indications in diabetic retinopathy.326 The need for reoperation following vitrectomy for diabetic traction retinal detachment generally

ranges from 24 to 47% (excluding laser and cataract

extraction).49,313,318,319

Chronic TRD involving macula (>6 months duration) is managed conservatively.69,71 In one study, macula-off TRD of greater than 1 month duration was associated with poor visual prognosis (<20/200, P ¼ 0.042, univariate analysis).325 In eyes with chronic macular detachment, the retina is atrophic beneath tightly adherent fibrovascular

membranes, which lower the potential for successful surgery.18,285

Combined traction–rhegmatogenous retinal detachment: PDR may cause severe fibrovascular proliferation resulting in progressive traction and posterior retinal breaks.327 The resultant retinal detachment appears different from TRD. Combined traction–rhegmatogenous retinal detachments (TRRD) appear convex and often extend anteriorly to the ora serata.120 The retinal often

has hydration lines, white lines in the inner retina, which are diagnostic of a retinal break (Fig. 9.14).285 Subretinal hemorrhage may be present.328 There is usually a single, small, paravascular retinal break

near posterior fibrovascular proliferation, often not identified until surgery.120,317,329 Silicone oil tampo-

nade is frequently used, especially in patients with poor vision in the fellow eye.120,330 Silicone oil

reduces the incidence of postoperative rubeosis and phthisis.120,330 Early reports of retrospective

consecutive series demonstrated retinal reattachment in 47–82% and improvement in vision in 20–53% of operated eyes with final visual acuity

of 5/200 or better in 55–68% of all eyes operated.32,317,329,331,332 With the availability of silicone

oil, subsequent studies reported retinal

Fig. 9.14 Combined traction–rhegmatogenous retinal detachment from PDR. The fundus photograph shows the convex nature of the retinal detachment with hydration lines within the retina. Preretinal hemorrhage obscures the view of the macula

reattachment in 73–93% and an improvement in vision in 64–81% of eyes following vitrectomy

with final visual acuity of 5/200 or better in 55–68% of all eyes operated (Table 9.8).330,333–335

To achieve these results reoperation was required in 29–90% of eyes.49,120,329,330,334 The incidence of

phthisis decreased from 8 to 10% in early, large

series to 0% with the use of silicone oil in later series.49,120,329,330 Favorable factors for postopera-

tive vision >5/200 include preoperative vision

>5/200, no NVI, no macular involvement, and no iatrogenic break.32,120

Severe fibrovascular proliferation: The progressive proliferation of fibrovascular preretinal tissue may occur despite photocoagulation, especially in poorly controlled type 1 diabetes.70 Without surgical intervention, severe fibrovascular proliferation (FVP) threatens profound loss of vision.285 The DRVS reported the natural history study of 142 eyes with severe FVP (NV >4DA with elevation of the border of the NV from traction, but no significant VH or TRD) and showed the percentage of eyes that developed severe visual loss at the 2-year follow-up increased from 0 to 32%. A majority of eyes (52%) suffered a loss of acuity of two or more lines mostly within the first year. The percentage of eyes with good vision ( 20/40) decreased from 57 to 39%. Visual acuity at baseline was a significant negative risk factor; eyes with <20/40 vision at baseline deteriorated to <5/200 at 2 years in

approximately 40% of cases. In interpreting this data, however, it should be noted that 73% of these eyes had no PRP at baseline, and by the 2- year follow-up, the percentage of eyes without any PRP was 35.9%.336 Today, more aggressive application of PRP likely improves the outcome in this cohort.69

The DRVS developed the definition of ‘‘advanced, active, neovascular or fibrovascular proliferation’’ (AA-PDR) from a review of the natural history study referenced above. They randomized to early vitrectomy vs. conventional management 370 eyes with useful vision ( 20/400) and AA-PDR. At the 4-year follow-up exam, good vision ( 20/40) was present in 44% of eyes in the early vitrectomy group compared with 28% of the conventional group (observation until TRD involved the macular or nonclearing VH >6 months) (P < 0.05). There was no reported difference between the two groups regarding risk of poor vision from surgical intervention. The final rate of severe visual loss was similar in the two groups. The benefit of surgery tended to increase with increasing severity of neovascularization (borderline statistical significance). Significant favorable factors included better vision at baseline and preoperative PRP laser.

Thus, the DRVS recommended early vitrectomy for eyes with any one of the following characteristics diagnostic of AA-PDR: (1) severe new vessels and severe fibrous proliferations; (2) severe new vessels and red vitreous hemorrhage; or (3) moderate new vessels (standard photo 10A, Fig. 9.1), severe fibrous proliferation, and red vitreous hemorrhage. Severe new vessels were defined as (1) NVD equaling or exceeding standard photograph 10C (Fig. 9.15) or (2) NVE equaling or exceeding standard photograph 7 (Fig. 9.16) in at least one 308 photographic field or (3) total new vessels (NVD and all NVE) summed over all photographic fields estimated to equal or exceed four disk areas. The DRVS concluded that eyes most suitable for early vitrectomy were those with both severe fibrous proliferation and at least moderately severe NV despite extensive PRP or hemorrhage precluding such treatment.69,337 Severe fibrous proliferations were defined as (1) fibrovascular proliferations on or within one disk diameter of the disk

border (FVD) equaling or exceeding two disk areas, or (2) fibrous proliferations elsewhere (FVE) equaling or exceeding standard photograph 11 (Fig. 9.17) in at least one photographic field, or (3) total fibrous proliferations (FVD and FVE) equal to or exceeding four disk areas.

Others have reported favorable surgical results for severe fibrovascular proliferation as well. In retrospective series, stable or improved vision was reported in approximately 78% of cases. Final vision >5/200 was reported in 81–82% of operated eyes.290 Favorable prognostic factors include young

Fig. 9.15 Standard photograph 10C defining the lower limit of severe new vessels on or within one disk diameter of the disk (printed with permission from the Early Treatment Diabetic Retinopathy Study Research Group. All rights reserved)

Fig. 9.17 Standard photograph 11 defining the lower limit of severe fibrous proliferation elsewhere (>1 disk diameter from the disk border) (printed with permission from the Early Treatment Diabetic Retinopathy Study Research Group. All rights reserved)

Fig. 9.16 Standard photograph 7 defining the lower limit of severe NVE (NV >1 disk diameter from disk border) (printed with permission from the Early Treatment Diabetic Retinopathy Study Research Group. All rights reserved)

age (<40 years), good preoperative vision (>5/200),

no NVI, preoperative PRP, and no iatrogenic break at surgery.183

From the literature we conclude that these cases are best managed with extensive PRP laser prior to early vitrectomy, which is best undertaken prior to

the development of extensive, strong vitreoretinal attachments.285,338 As some eyes lose vision despite

surgery, it is essential to counsel the patient regarding the benefits and risks of surgery vs. natural

history. These issues are of particular importance in patients with relatively asymptomatic pathology.

Diabetic macular edema: The reader is referred to Chapter 7, which includes a discussion of vitrectomy for diabetic macular edema.

Postvitrectomy fibrinoid syndrome with retinal detachment: The syndrome of intraocular fibrin deposition following diabetic vitrectomy is discussed under the section on complications of vitrectomy surgery later in this chapter. Repeat vitrectomy surgery may be attempted in severe cases with secondary traction retinal detachment and neovascular glaucoma, but the prognosis is poor.285 Adjunctive use

of steroids and tissue plasminogen activator may improve success rate.285,339–341

Anterior hyaloidal fibrovascular proliferation (AHFVP): The growth of fibrovascular tissue on the anterior vitreous base in PDR is a severe complication following vitrectomy.342,343 If progressive membranes cause retinal detachment, ciliary body detachment, or neovascular glaucoma, repeat vitrectomy surgery may be indicated.285 The reader is referred to the subsequent section on complications of vitreoretinal surgery for further details.

A less rapidly progressive form of AHFVP has been described after cataract extraction in nonvitrectomized eyes. Risk factors included PDR, iris rubeosis, and ischemic anterior retina. Delayed onset

was noted at an average of 12 months following cataract surgery and no progression was noted over an average 6-month follow-up. Vision was rarely affected and no complications of vitreous hemorrhage or traction detachment were reported.343

Vitreomacular interface pathology: Epiretinal membranes (ERM), macular hole, vitreomacular traction syndrome, and other vitreoretinal interface disorders are encountered in patients with or without diabetes. However, there may be unique features in the presentation, management, and out-

come with vitrectomy in patients with diabetes mellitus.344–347

Epiretinal membranes in PDR may be vascular or avascular.348,349 Below is a discussion of avascu-

lar, premacular, epiretinal membranes associated with diabetic retinopathy. Although pathogenesis of ERM in diabetic retinopathy shares some features with idiopathic ERM, the role of fibrogenic

growth factors maybe greater in diabetic ERM.25,26,350,351 In addition, the cellular and extra-

cellular composition of ERM varies with underlying etiology.352,353 The proliferative activity of diabetic ERM may be greater than the idiopathic variety.354 In preparation for surgery, optical coherence tomography demonstrates the variable vitreoretinal relationships seen with diabetic ERM.355 Diabetic ERM is more likely to have focal rather than global attachments to the macula compared to idiopathic ERM (P ¼ 0.007).356 Factors associated with visual improvement after membrane peeling in PDR include age and preoperative visual acuity.348 Concomitant peeling of internal limiting membrane

(ILM) may improve macular appearance on OCT349 and improve visual outcome.349,357 How-

ever, peeling of ILM in eyes with diabetic macular

edema may rarely be associated with macular hole formation.358,359

In general, the presentation of macular holes in patients with diabetes may be similar to those without diabetes. The causative mechanism of macular hole appears to be tangential vitreous traction, although diabetic macular edema may play an additional causative role in diabetic retinopathy.360,361 Macular holes may form in association with PDR alone (Fig. 9.18) or following bevacizumab injec-

tion, triamcinolone injection, or vitrectomy surgery with or without peeling of the ILM.272,359,362,363

Complex vitreoretinal attachments may be

Fig. 9.18 Macular hole due to fibrous proliferation and contraction in PDR

encountered with fibrovascular proliferation at the

macular hole, which may result in retinal detachment.32,364,365 Peeling of ILM may be difficult and

unnecessary for successful closure of macular hole in cases of moderate or high macular detach-

ment.364 The rate of successful closure of macular

hole is 73–100% (Table 9.9).344–347,360,362,364,366,367

The visual prognosis correlates negatively with poor preoperative visual acuity, increased degree of macular detachment, increased severity of diabetic

retinopathy, and the presence of submacular hemorrhage.344–346,346,347,364 Generally, there is

only limited visual improvement following repair of macular hole associated with proliferative diabetic retinopathy. Spontaneous closure of macular hole with PDR may occur.368

Vitreomacular traction may present with complex vitreoretinal adhesions potentially requiring more extensive vitrectomy surgery than that required in non-diabetic patients (Fig. 9.19). The intact posterior

hyaloid may be taut in cases of ERM and macular edema.369–371 Progressive contraction of the intact

cortical vitreous may result in traction retinoschisis.372 Alternatively, tangential traction may result

in macular heterotopia as a cause of decreased acuity, metamorphopsia, and diplopia.27,30,369,373–378

Controversial indications for vitrectomy: Vitreopapillary traction (VPT) is a relatively new and

equivocal indication for diabetic vitrectomy with proponents in Europe.183,379–381 VPT occurs as a

result of anomalous posterior vitreous detachment.

Fig. 9.19 Optical coherence tomograph of right eye (20/40) with established PDR demonstrating incomplete separation of vitreous with multiple vitreoretinal attachments

The macromolecular changes that result in vitreous gel liquefaction occur without concurrent separation of the posterior cortical vitreous from the surface of the optic disk.382 The optic disk may appear elevated and hyperemic with blurred margins due to condensation of the overlying vitreous or due to traction on the disk and peripapillary retina.383 Optical coherence tomography is useful to confirm the diagnosis.384,385 Vitreopapillary traction has been described as an isolated phenomenon or in

association with other pathology, including diabetic retinopathy. Among those cases without diabetic retinopathy, VPT may occur in young patients in whom myopia may induce vitreous liquefaction and mildly dyplastic optic disks may contribute to unusual vitreopapillary adherence.386,387 Although most patients are asymptomatic despite the pre-

sence of intrapapillary and peripapillary hemorrhage,386,387 gaze-evoked amaurosis may occur.388

Generally, VPT remains stable with follow-up and does not require intervention.386,387 However,

macular exudates presenting as a stellate maculopathy may rarely develop in association with peripapillary traction detachment in VPT.389 In older patients with involutional vitreous degeneration, persistent vitreopapillary adhesion of unknown cause may result in VPT. These patients usually present without symptoms and may be detected on fluorescein angiography with disk staining.390,391 However, symptomatic vitreomacular traction and

traction macular detachment may complicate VPT.384,385 Ischemic central retinal vein occlusion

has been reported to cause VPT; however, the