retinal detachment.285,617 Intraoperative risk factors included the use of gas for internal tamponade and creation of iatrogenic retinal break.617 The long-term outcome after vitrectomy is good for up

to 10 years in eyes with good vision and attached retina at the 6-month visit.69,618–620

9.5 Follow-Up Considerations in PDR

Evaluation and management of proliferative diabetic retinopathy over the course of time requires extensive consideration of systemic and ocular factors and the appropriate use of diagnostic testing. Systemic factors include assessment of blood glucose and blood pressure status, extraocular diabetic complications, cardiovascular health, renal function, serum lipid levels, fluid retention, psychological status, pregnancy, medications, and visual needs. Complete routine ocular examination is of paramount importance.

Follow-up interval: The interval between office visits will be determined by the aforementioned factors. Daily to weekly visits are warranted in severe PDR with active neovascularization, e.g., neovascular glaucoma. Monthly to quarterly visits are reasonable as PDR stabilizes. After PRP is complete and NV has regressed, annual visits may be considered for metabolically stable patients.

Pregnancy is associated with progression of PDR. Follow-up examination each trimester or more often is recommended to detect and treat PDR. Diabetic retinopathy tends to stabilize after pregnancy and no long-term severe adverse effects are reported in patients who become pregnant compared to those who do not. Factors for increased risk of progression during pregnancy include duration of diabetes, degree of metabolic control, extraocular complications

of pregnancy, and severity of retinopathy at conception.104,621,622

Ocular factors that may increase the rate of progression and need for close follow-up include intraocular inflammation and cataract surgery.623–627

Refer to the Section 9.6.6 on conditions affecting the presentation of PDR.

Ancillary testing: Complete slitlamp examination with fundoscopy is the primary method of

evaluation; however, ancillary testing may be useful in selected circumstances. Especially in patients who have difficulty in maintaining visual fixation, serial photography helps identify progression of diabetic retinopathy.628 Fluorescein angiography is not required to initiate treatment of PDR, but may be helpful in difficult cases. For example, fluorescein angiography may confirm the presence of suspected new-onset neovascularization presenting with vitreous hemorrhage.629,630 Fluorescein angiography may also help determine the cause of

decreased vision by demonstrating macular capillary dropout.629,631

Optical coherence tomography (OCT) provides useful information in the management of diabetic retinopathy. OCT demonstrates retinal thinning in macular ischemia/atrophy, cystic spaces in macular edema, retinal thickening and surface irregularity

with preretinal membrane, and retinal elevation in cases of vitreoretinal traction.371,390,632–635 Diffi-

culty remains in determining the relative significance of these changes as they relate to visual function, especially in eyes with multiple pathological changes.

Visual field examination by perimetry may be considered in evaluating for driver safety. Although visual acuity may be acceptable, visual field may be compromised to an unsafe degree for driving in patients with advanced PDR.636

9.6Case Management: Decision-Making in Complicated Cases

9.6.1 Cataract and PDR

The coexistence of cataract and PDR is common and requires special consideration.637 Chapter 10 reviews this issue for diabetic retinopathy in general. This section identifies specific issues as they relate to proliferative disease. Although cataract may interfere with visual function and evaluation of the retina, only rarely does cataract interfere with

laser placement, especially with the availability of long wavelength (red) laser.146,147 When cataract

extraction is indicated, the timing of surgery depends on the activity of the PDR.

Optional strategies depend on the relative severity of the cataract and PDR, as well as the presence of

macular edema. The visual prognosis is guarded in this group of eyes.624,638 In general, PDR is treated

with PRP before cataract surgery, but laser may be given by indirect ophthalmoscopic delivery at the time of cataract surgery or at the slitlamp promptly after surgery.639 There is limited information on the optimal sequence of PRP and cataract extraction with regard to the risk of loss of acuity and macular edema.640 Results of cataract surgery with untreated PDR are poor and fraught with progression of PDR and early post-cataract laser may be difficult due to

pain, inflammation, corneal edema, and wound con- cerns.641–643 However, in a small randomized trial,

PRP after cataract extraction was associated with reduced loss of acuity (P ¼ 0.012) and less macular edema (P ¼ 0.033) 12 months after surgery compared with the fellow eye that underwent PRP before cataract extraction.640 If PRP is indicated, but not possible due to poor view through cataract, triamcinolone acetonide or anti-VEGF agents may be injected for short-term stabilization for cataract sur-

gery until laser can be applied postoperatively.218,260,261 These same agents may be helpful in

the short-term management of macular edema exacerbated by cataract surgery.219,644 Intraocular VEGF and other cytokine levels are elevated following diabetic cataract surgery.645 Poor metabolic control is associated with an increased risk of progression of diabetic retinopathy after cataract surgery.646 However, efforts to improve short-term worsening of diabetic retinopathy and maculopathy by rapid improvement in glycolic control prior to cataract extraction appear to be ineffective, if not harmful.647

If vitrectomy surgery is indicated, cataract surgery before or during vitrectomy lowers the rate of repeat vitrectomy compared to phakic vitrectomy,

possibly due to improved access to the peripheral retina in the non-phakic eye.314,330,648,649 Sequential

cataract surgery followed by vitrectomy has the disadvantage of two separate visits to the operating suite, but may diminish the inflammation and complications seen with combined surgery.650 Sequential surgeries may be facilitated by the use of triamcinolone acetonide and anti-VEGF injection as noted above.

Cataract extraction at the time of vitrectomy may speed the recovery of vision in selected

cases.314,651 Extracapsular cataract extraction or phacoemulsification with posterior chamber lens implantation may be combined with vitrectomy surgery.652 However, there appears to be an increased rate of intraoperative lens capsular tears and zonulysis as well as postoperative inflammation, poster-

ior synechiae formation, and posterior capsular fibrosis.314,548,650,653 A poor red reflex in eyes with

vitreous hemorrhage makes cataract surgery more challenging.314 Combined procedures with extracapsular cataract extraction appear to create more inflammation than with phacoemulsification.551 Aggressive management of inflammation is needed with consideration for the use of triamcinolone

injection, which may also help control the increased incidence of macular edema.654–656 Combined pha-

coemulsification/vitrectomy may be especially suitable in a patient presenting with cataract and indications for diabetic vitrectomy in the presence of poor vision in the fellow eye.314

Combined vitrectomy with pars plana lensectomy is another alternative. This approach involves less anterior segment manipulation and, therefore, may cause less anterior chamber inflammation. The anterior capsule may be retained for the placement

of a ciliary sulcus lens implant at the time of vitrectomy or subsequently.657–660 This approach has been

reported to be successful in highly complicated cases with combined traction–rhegmatogenous retinal detachment requiring silicone oil injection.330 Limited data show no definitive advantage of pars plana lensectomy compared with trans-corneal phacoemulsification.661,662 However, there may be less anterior chamber inflammation and fibrin deposition associated with pars plana lensectomy.552

Cataract surgery performed on an elective basis after vitrectomy generally produces improved vision. However, capsular tears and zonulysis complicate surgery in approximately 10% of cases,

increasing the risk of posterior dislocation of lens fragments or lens implant.650,663

Regardless of the relative timing of cataract and vitrectomy surgery, complications may occur. Postoperative anterior capsular contraction occurs more often in eyes with diabetic retinopathy and may

result in traction on the ciliary body with hypotony and ciliary effusion.664,665 With appropriate use of

PRP, the risk of rubeosis and neovascular glaucoma is minimized. The ETDRS reported NVI/NVG in

6% of eyes after cataract extraction.69,666 Small retrospective studies report similar low incidence of NVI/NVG, the risk of which correlates directly

with the severity of PDR and indirectly with the amount of PRP.69,667,668 With meticulous attention

to completing PRP including the anterior periphery, the incidence of NVI/NVG may be decreased to less than 1%.314 Finally, the risk of retinal detachment of approximately 5% following diabetic vitrectomy

appears to be unaffected by the addition of cataract extraction.314,585

In the ETDRS, the visual outcome is related directly to the severity of diabetic retinopathy. Two hundred and seventy eyes were studied prospectively. One-year after cataract surgery, 55% of eyes with advanced diabetic retinopathy (severe NPDR or worse) experienced improved vision. The distribution of visual acuities in this group was as follows: 25% >20/40, 42% >20/100, and 22% 5/200 or worse.666 Others estimate that patients with PDR are 30 times less likely to achieve 20/40 or better vision compared with diabetic patients without retinopathy. Compounding the problem is evidence that some patients with advanced PDR who undergo phacoemulsification may not experience improved visual function despite improvement in measured visual acuity.669

The effect of cataract surgery on progression of diabetic retinopathy is uncertain. The ETDRS showed a trend of borderline significance toward short-term worsening of diabetic retinopathy. The study showed no long-term increased prevalence of diabetic macular edema, but the study was not designed to detect an early increase in macular edema or an increase in severity of edema in the long term.666 Others have provided conflicting evidence of progression of diabetic retinopathy after cataract surgery (for further discussion the reader is referred to Chapter 10).

9.6.2Dense Vitreous Hemorrhage and Untreated PDR

The presence of dense vitreous hemorrhage in an eye with untreated PDR not only causes acute severe loss of vision but also places the eye in a

category at high risk for potential persistent visual loss.65,66,102 There are several options to reach the

goal of clearing the vitreous hemorrhage and applying PRP. Elevation of the head at night or patching with strict bed rest may help clear the hemorrhage for office-based PRP.287 Anti-VEGF agents may be injected to cause short-term involution of neovas-

cularization while waiting for hemorrhage to clear.210,263 Purified ovine hyaluronidase has been

shown to speed the resolution of vitreous hemor- rhage.277–279 The status of the vitreous may play a

role in the decision to intervene with vitrectomy. If a complete PVD is present, observation may be pre-

ferable to vitrectomy, especially if the fellow eye has good vision.38,74 If severe PDR is suspected based on

the history of type 1 diabetes, iris neovascularization, or extensive vitreoretinal traction seen on B-scan, early vitrectomy is indicated.69,74 Previtrectomy intravitreal injection of bevacizumab may be considered prior to surgery in these high-risk cases.248 On the other hand, the echographic finding of tractional retinal detachment may argue against anti-VEGF therapy.273 If vitrectomy is necessary, even partial preoperative PRP may improve outcome.184

9.6.3Untreated PDR with Diabetic Macular Edema

The presence of diabetic macular edema in eyes with PDR is indicative of increased severity of retinopathy with increased risk of retinopathy progression and severe visual loss compared to eyes with the same stage of retinopathy without edema. Panretinal photocoagulation (PRP) is useful to prevent profound loss of vision in PDR, but may increase macular edema and decrease visual acuity in a doserelated fashion.67 For eyes with high-risk PDR, the ETDRS recommended macular focal/grid laser for clinically significant macular edema (CSME) at the initial session with the option of starting PRP for PDR in the nasal quadrants during the same session. PRP in the temporal quadrants was deferred for at least 2 weeks.68 The ETDRS cautioned against delaying PRP for high-risk PDR with CSME. For eyes approaching, but not reaching high-risk PDR, the peripheral scatter treatment was not started until the edema had resolved after

which ‘‘mild scatter’’ (lower density, fewer burns) treatment was applied. Retreatment in these eyes was only given if progression in retinopathy was documented. This treatment plan was shown to reduce the rate of severe visual loss compared to deferral of treatment.67

Small studies show that intravitreal triamcino-

lone decreases macular thickening and prevents worsening of vision after PRP.221,670–674 A small,

randomized, controlled, clinical trial demonstrated a significant benefit of triamcinolone acetonide in preventing decreased vision and increased macular edema following PRP and focal laser for eyes with PDR and CSME.221 The benefits of this treatment must be balanced by the risks including cataract, glaucoma, and endophthalmitis.211 An alternative to prophylactic treatment is rescue treatment with triamcinolone acetonide after PRP treatment if macular edema worsens with decreased vision. However, triamcinolone acetonide may be considered primarily as an adjunct to macular focal laser in the treatment of diabetic macular edema.233 AntiVEGF agents may be considered for a similar adjunctive role in the management of these difficult cases.241 This topic is also discussed in Chapter 7.

9.6.4PDR with Severe Fibrovascular Proliferation/Traction Retinal Detachment

There is an established role for early vitrectomy in the management of severe fibrovascular proliferation (FVP) and traction retinal detachment (TRD).72 Pan-

retinal photocoagulation improves outcome despite

potential short-term risks. 17,49,69,176,183,184,406,407

Open to question is the role of anti-VEGF therapy. Although some have reported beneficial results with bevacizumab in these cases, there is anecdotal evi-

dence of progression of TRD with anti-VEGF injection.243,272,273 Until further research allows for risk

stratification, bevacizumab should be used with caution. In cases of severe traction detachment with or without rubeosis, silicone oil tamponade may be useful for prolonged tamponade and for sequestration of fibrovascular growth factors until laser treatment has taken effect.442

9.6.5 PDR with Neovascular Glaucoma

Panretinal photocoagulation and peripheral retinal cryopexy play a key role in the management of active

new vessel growth in neovascular glaucoma (NVG).285,675 Extensive PRP is needed to treat the

widespread areas of capillary dropout in these cases.17 Indeed, prevention of NVG with appropriate timing and extent of PRP is preferable to treating established NVG.69 New to the armamentarium are the anti-

VEGF agents, which cause dramatic short-term resolution of neovascularization.248–250,267,269,270 Their

role may be best suited to minimize progression of angle neovascularization and secondary synechiae formation while peripheral laser/cryopexy takes effect.210 Retinal detachment is associated with rubeosis and repair of the detachment may induce regression of the rubeosis.676 Retinal tamponade with silicone oil is useful in these cases.442

When significant anterior synechiae block the trabecular meshwork, intervention is directed at destruction of the ciliary body to decrease aqueous production or at providing alternative routes for aqueous drainage. Surgery may lower IOP, but visual prognosis is grim.69 Many surgical procedures are available to lower IOP, some of which are employed by the vitreoretinal surgeon. The reader is referred to Chapter 11 for further discussion.

9.6.6Conditions Altering the Clinical Course of PDR

‘‘Early worsening’’ with improved metabolic control: The primary issue in managing rapid worsening of diabetic retinopathy is identifying conditions in which rapid worsening might occur and initiating prompt treatment with PRP. Although improved metabolic control is associated with improved long-term outcome, ‘‘early worsening’’ was described in patients assigned to tight control in the Diabetes Control and Complications Trial.8 The effect of early worsening of diabetic retinopathy was reversed by 18 months and did not result in serious visual loss.6 Successful pancreas transplant

surgery leads to improved control with the potential for short-term worsening of retinopathy.677–681

Pregnancy: There is an increased short-term risk of progression of diabetic retinopathy with pregnancy. The increased risk may continue for up to 1 year, but no long-term adverse effects of pregnancy were reported by the Diabetes Control and Complications Trial.106 Additional factors that may increase the risk of progression in pregnancy include duration of diabetes (>10–15 years), poor glycemic control, hypertension, and

the presence of moderate–to-severe NPDR at baseline.105,682 Therefore, prompt PRP is indi-

cated in pregnant patients with severe NPDR or early PDR.69

Carotid atherosclerosis: Atherosclerosis of the carotid artery may affect retinal vascular perfusion by embolization or stenosis.683 Emboli may be liberated from an atherosclerotic plaque and occlude the central retinal artery or a branch retinal arteriole. In the presence of diabetic retinopathy, this added ischemic insult may

precipitate neovascularization (Fig. 9.32).50,684–687 Alternatively, if profound neurosensory apoptosis results from central retinal artery occlusion prior to the onset of diabetic retinopathy, there may be a protective effect against progression of diabetic retinopathy (Fig. 9.33).

There are conflicting reports regarding the effect of carotid stenosis on diabetic retinopathy. Most recent reports indicate carotid stenosis is associated

with ipsilateral worsening of diabetic retinopa- thy.173,688–691 However, relative ipsilateral sparing

from diabetic retinopathy has also been described.692–696 A possible explanation for these conflicting reports is presented in the Box. Systemic evaluation of patients presenting with asymmetric diabetic retinopathy may include non-invasive carotid Doppler ultrasonography. However, only a minority of patients with asymmetric diabetic retinopathy test positive for significant carotid occlusive disease.690

Fig. 9.32 Apparent asymmetric diabetic retinopathy. Ischemic retinal whitening superior to left disk (a) due to branch retinal artery occlusion with symptomatic inferior visual field loss. Mild NPDR is seen on fluorescein angiogram (b) along with delayed circulation time in superior

hemispheric retinal vasculature. Several months later, the patient returned with further loss of vision OS due to vitreous hemorrhage from disk neovascularization (d). The right eye had mild NPDR (c). Note: photographic artifacts are seen centrally in macula OS and near disk OD

Fig. 9.33 Asymmetric diabetic retinopathy. Right eye (a) suffered from profound loss of vision many years ago due to central retinal artery occlusion with resultant pale disk and attenuated arterioles. Subsequently, less severe retinopathy

developed in the right eye compared with the left eye (b), which had progressed to high-risk PDR requiring panretinal photocoagulation

Neovascular glaucoma in diabetes may be caused by PDR or ocular ischemic syndrome (OIS). Findings suggestive of OIS as the primary cause include an unexpected low intraocular pressure and ipsilateral bright-light amaurosis, both likely due to poor ocular perfusion.700–703 Revascularization of the occluded carotid artery may result in improved vision. However, complications may be encountered with improvement in perfusion. For example, an abrupt increase in intraocular pressure may occur

following carotid surgery if extensive posterior synechiae are present.691,701,704 Rarely, diabetic macular

edema becomes manifest after endarterectomy.705

Miscellaneous ocular and systemic conditions: A variety of ocular conditions may affect PDR.

Conditions associated with extensive destruction or thinning of the retina provide protection against the development of PDR. They include high myopia, previous central retinal artery occlusion (Fig. 9.33), advanced glaucoma (Fig. 9.34), optic atrophy, rod–

cone degeneration, and extensive chorioretinal scarring from trauma or past inflammation.13,172,173,706

Asteroid hyalosis may increase the risk of developing PDR, probably due to the associated lower prevalence of posterior vitreous detachment.38,173

Ocular inflammation generally appears to accelerate diabetic retinopathy in conditions such as anterior

uveitis, posterior uveitis, surgery, and endophthalmi- tis.623,625–627,643,707 A possible link is the common

elevation of cellular fibronectin and adrenomedullin