Table 11.3 Risk Factors for Angle Neovascularization

Data from Hamanaka et al.62 The relative risk means risk when this factor is present compared to the case when it is not present.

Not only does lensectomy during vitrectomy increase the odds of postoperative development of NVI, if an eye has preoperative NVI and undergoes vitrectomy, the odds of postoperative regression of NVI decrease from 55 to 28% if an intraoperative lensectomy is performed.95

11.7Entry Site Neovascularization After Pars Plana Vitrectomy

Entry site neovascularization after pars plana vitrectomy for proliferative diabetic retinopathy has been reported to occur in 18% of sclerotomies. Three configurations of proliferations have been

described – spheroidal, tent shaped, and trapezoidal. The trapezoidal configuration is associated with the highest incidence of clinically important postvitrectomy vitreous hemorrhage requiring vitreous cavity washout. Rates for requiring vitreous cavity washout

of postvitrectomy hemorrhage have ranged from 7.5 to 23.7% over 6 months of follow-up.64,96 These

rates are probably influenced by the case mixes of the eyes in the series. Unlike the situation with iris neovascularization, a possible confounding variable is the presence of vitreous incarceration in the entry site acting as a scaffold for proliferation. Surgeons generally make special efforts to prevent this occurrence by using maneuvers such as scleral depression to better view and access the vitreous base during surgery, and sometimes simultaneous cataract surgery to allow better access to this location. Other steps used to minimize the occurrence of entry site neovascularization include near-conflu-

ent laser photocoagulation to the anterior retina or peripheral retinal cryotherapy.64,120,121 Iris neo-

vascularization is sometimes associated with cases of entry site neovascularization.122,120

11.8Anterior Hyaloidal Fibrovascular Proliferation

Anterior hyaloidal fibrovascular proliferation is the most common severe postoperative complication following vitrectomy for diabetic retinopathy occurring in approximately 13% of eyes within the first 12 months after vitrectomy. Neovascularization originating from the anterior retina grows into the anterior hyaloid and extends along the posterior lens surface causing early recurrent vitreous hemorrhage, cataract formation, peripheral retinal traction detachment, ciliary body detachment with hypotony, and often progressing to phthisis bulbi.97,98 The typical patient developing this complication is a young male with poorly controlled diabetes mellitus, severe retinal ischemia, and frequently traction retinal detachment. Placement of a scleral buckle may increase the frequency of this complication.97 Early recognition with lensectomy, repeat vitrectomy with aggressive dissection of anterior fibrovascular membranes, placement of confluent panretinal laser photocoagulation up to the ora

serrata, and sometimes instillation of silicone oil may salvage such eyes.97

11.9Treatments for Iris Neovascularization

The foundation for treatment of iris neovascularization is panretinal photocoagulation, which

destroys ischemic retina and leads to reduced intraocular production of VEGF.59,63,84,117,123

Although often effective, and differentially effective in NVI associated with diabetic retinopathy as opposed to central vein occlusion, PRP is not uni-

versally effective, and its effect is not immediate.84,124,125 The effect of PRP is dose dependent.125,126 Full PRP is more effective than partial PRP in causing regression of NVI.125,126 Occasion-

ally there is insufficient time for the effect of PRP to develop before irreversible damage such as angle synechia and optic atrophy from elevated pressure supervenes.127 In these cases, a regression of neovascularization within 24 h can be effected by intra-

vitreal or intracameral injection of bevacizumab or another anti-VEGF agent (Figs. 11.12a and b).128–132

Bevacizumab is also helpful in cases in which PRP fails to cause regression of NVI.128,129This regression

of NVI can boost the success rates of filtering sur-

geries, but the effects vanish as the drug leaves the eye, usually within 6 weeks.128,133 Bevacizumab is

best viewed as a bridge to allow more complete and sustainable reduction in intraocular VEGF concentrations through PRP or cryotherapy. Bevacizumab alters wound healing, reduces postoperative bleed-

ing, and may augment the effectiveness of filtering surgery through these mechanisms.128,133 Photody-

namic therapy of NVI with intravenous verteporfin has also been used as a treatment to cause regression of NVI and prevent angle closure while the effect of PRP takes effect.127 In some cases with vitreous hemorrhage precluding a view for office PRP, regression of NVI can be effected by vitrectomy with endolaser photocoagulation, or in eyes with poor visual

potential, transscleral cryotherapy, or transscleral diode laser photocoagulation.124,134–136

The outcome of treatment of NVI and NVA is related to the severity of the anterior segment signs present before treatment. In general, the more

extensive the PAS, the less likely that intraocular pressure control can be achieved with retinal ablation and medical therapy. For eyes with no PAS, 94% show regression of NVI with PRP and 12% have persistent elevation of IOP. For eyes with <270 degrees of angle closure, 25% have persistent IOP elevation after peripheral retinal ablation. Of eyes with >270 degrees of PAS, persistent IOP elevation was present in 67% of eyes.88

A subset of eyes with NVI progress to neovascular glaucoma. These eyes frequently require filtering surgery or tube shunt surgery to control the intraocular pressure. Adequate preoperative PRP and induced regression of anterior segment neovascularization are considered important to increase the chance of success of these procedures.137 Presence of active intraocular neovascularization and presumptively elevated VEGF levels are thought to produce an exaggerated woundhealing response that mitigates the effectiveness of glaucoma surgery.138

In experimental models of NVI, systemic a-inter- feron injections and intravenous injections of squalamine, an antiangiogenic aminosterol, led to

regression of NVI and prevention of NVI, respectively.139,140 The side effects of interferon therapy in

humans for other indications have been significant, and this experimental result has not translated into a practical treatment in human disease. Intravenous squalamine therapy has been tested in a phase 1 clinical trial for neovascular age-related macular degeneration, but has not been used in NVI.

11.10Modifiers of Behavior of Iris Neovascularization

Removal of the lens in eyes with diabetic retinopathy undergoing vitrectomy surgery has traditionally been considered to raise the risk of subsequent development of NVI, but more recent reports in

the era of endolaser photocoagulation suggest that this traditional teaching is no longer true.119 In modern series, rates of postoperative development of NVI following vitrectomy surgery have been <5% whether the eyes are phakic or pseudophakic.119 The postoperative NVI in these cases typically regresses with office PRP.119

Iris neovascularization secondary to diabetic retinopathy progresses less rapidly and responds better to PRP than that following retinal venous occlusions.88 Because patients with diabetic retinopathy can have concomitant retinal venous occlusive disease, awareness of this relationship is important, and follow-up interval and heaviness of treatment adjusted as needed in the presence of two conditions.

Carotid artery occlusive disease can exacerbate a tendency for an eye with diabetic retinopathy to develop NVI and, paradoxically, may ameliorate the tendency in some cases.

11.11Management of Neovascular Glaucoma

It was only a few decades ago that a textbook could say of neovascular glaucoma ‘‘the only practical treatment, if a retrobulbar injection of alcohol or cyclodiathermy fails to relieve the pain, is enucleation.’’133 Fortunately, the prognosis for patients with NVG is much less grim today. The management of neovascular glaucoma has evolved dramatically since then, especially over the past few years as the emerging role of anti-VEGF medications has come into better focus.

In evaluating a patient with neovascular glaucoma it is first critical to determine the cause of the new vessels, since definitive treatment of the underlying disorder, whether it is diabetes, ocular ischemia, uveitis, radiation, or some other condition, makes management of the glaucoma more successful and preservation of vision more likely.134 A dilated fundus exam is mandatory, and other studies including fluorescein angiography, noninvasive carotid ultrasound, or B-scan may provide additional useful information about the etiology.

Once the causative condition has been identified and addressed, the appropriate approach to a patient with neovascular glaucoma depends upon

the stage at which the disease presents. The essential diagnostic test in staging NVG is gonioscopy. In Stage 1 NVG, there is rubeosis or angle neovascularization but the angle remains open and the IOP is still normal. Stage 2 NVG has iris or angle NV with elevated IOP. Stage 3 NVG is characterized in addition by peripheral anterior synechiae, and some degree of irreversible angle closure.137 However, even before there are clinically visible peripheral anterior synechiae neovascular tissue can insinuate itself into intertrabecular spaces and disturb aqueous outflow.115 All three stages of NVG may be associated with anterior chamber flare, conjunctival injection, hyphema, or photophobia, but ectropion uveae, corneal edema, decreased vision, headache, and eye pain more frequently appear in the advanced stages.

In Stage 1 NVG, the priority is to induce the new vessels to regress before they cause angle closure. Until recently, this meant applying urgent panretinal photocoagulation, which can, within 3–6 weeks, lead to resolution of rubeosis.123 If the view of the retina is inadequate, other options include transscleral retina cryoablation or, more often, pars plana vitrectomy with endophotocoagulation, and possibly cataract extraction.

Now, however, the availability of medications to counteract the effect of VEGF has altered the therapeutic algorithm. An intravitreal or intracameral injection of an anti-VEGF medication such as bevacizumab can cause very rapid and long-lasting resolution of new vessels even before PRP can take effect. A growing literature, still mostly case reports and small series, attests to the utility of these medications in arresting the neovascular process and in causing rapid regression of the new vessels. The first case report appeared as recently as 2006. Avery reported regression of retinal and iris neovascularization when intravitreal bevacizumab was given after PRP. No side effects were noted.71 Since

then, many other reports have confirmed this impression.72,136–143 Typical are the findings

reported by Wakabayashi et al., whose large series of 41 eyes showed that intravitreal bevacizumab often leads to complete regression of neovascularization within a week.144 Although many eyes had recurrent rubeosis within 6 months, beginning on average after 2 months, repeat injections were usually effective. In eyes with elevated IOP but

open angles, the typical result of a single injection was not only regression of rubeosis but also normalization of IOP within a week as well. Eyes with synechial angle closure due to NVG had resolution of rubeosis but no improvement in IOP. MartinezCarpio surveyed the burgeoning literature in this area.145 In the 26 articles he compiled, none of which were randomized studies, the use of intravitreal bevacizumab injections for NVG was associated with no systemic complications and less than 1% ocular complications.

This medication may also be given as an intracameral injection with similarly dramatic reduc-

tions in new vessels, IOP, and aqueous VEGF levels.130–132 When cultured human corneal

endothelial cells were exposed to a normal thera-

peutic concentrations of bevacizumab, no toxic effects were identified.146,147

It is uncertain whether such injections by either route are better given before, after, or on the same

day as PRP, since publications report rapid regression of NV regardless of the sequence.71,140,141 In

some eyes PRP may be easier to perform after new vessels have regressed, IOP has normalized, the cornea has cleared, and hyphema has resolved. But in general, when retinal ischemia is the cause of iris neovascularization, the sooner the underlying disorder can be treated the better, and PRP should be applied as soon as possible to begin to build a longterm solution upon the acute improvement that anti-VEGF medication can provide.

In Stage 2 NVG, which presents with rubeosis, elevated IOP, and open angles, the IOP needs to be controlled medically until the new vessels regress. Once the neovascular process has been arrested and reversed the IOP may return to normal, allowing glaucoma medications to be tapered and discontinued. As in Stage 1 NVG, the first priority is to treat the underlying cause of the rubeosis, to do aggressive PRP, and to consider injection of an antiVEGF medication either into the vitreous or into the anterior chamber. At the same time medications to lower the IOP and to control inflammation can be started to prevent optic nerve damage and to encourage corneal edema to clear, so the eye can be more fully examined.

Aqueous suppressants, such as beta-blockers, carbonic anhydrase inhibitors, and alpha-2

agonists, are all often effective. Prostaglandin analogues may also be helpful, but can aggravate inflammation in these eyes. Miotics (cholinergic drops) should not be used. The pain that NVG patients experience is just as often due to inflammation as to high IOP and may persist even after the IOP is controlled. It is also important to begin topical corticosteroid drops and cycloplegics to reduce inflammation, relieve pain, and stabilize the blood–aqueous barrier.

Patients presenting with synechial angle closure (Stage 3 NVG) will almost always have persistent elevated IOP even after their new vessels regress, and most soon require some sort of glaucoma surgery to lower IOP and preserve vision. In fact, whichever Stage NVG the patient has at presentation, if IOP cannot be controlled medically glaucoma surgery is indicated, but deciding upon the appropriate procedure depends upon the eye’s vision potential. Incisional surgery, such as trabeculectomy or a glaucoma drainage implant, is best reserved for eyes in which vision can be preserved. Nonpenetrating glaucoma procedures, such as viscocanalostomy or canaloplasty, are unlikely to be helpful in these cases, especially if the angle is closed. If vision is expected to remain very poor because of extensive retinal ischemia or advanced optic nerve damage, the risks of incisional surgery may not be acceptable, and a cyclodestructive procedure should be considered. Blind painful eyes may be treated with retrobulbar injections or by evisceration or enucleation.148 Each of these approaches will be discussed.

Trabeculectomy surgery has historically had a very poor success rate in neovascular glaucoma. Full PRP improves the prognosis for trabeculectomy, but the vessels may take several weeks to regress.149 Surgery in such eyes is complicated by excessive risk of inflammation and hemorrhage. Even with the help of 5-FU or mitomycin-C, the chance of long-term filtration is minimal in an eye with active rubeosis, since aqueous containing high levels of VEGF will leave the eye through the sclerostomy and promote neovascularization that can cause the bleb to scar. For this reason, many glaucoma surgeons have preferred to perform trabeculectomy with mitomycin for immediate IOP control soon after PRP, while at the same time placing a

glaucoma implant, expecting that the trabeculectomy would be scarring closed and beginning to fail by the time the temporary ligature around the implant tube opened after 1–2 months.

Recent reports of the adjunctive use of antiVEGF medications suggest that they may improve the outlook for filtration surgery in eyes with

NVG. Bevacizumab has been injected into the vitreous,121,127,150,128,133 into the anterior cham-

ber,151 and subconjunctivally152 to good effect.

These medications also have an inhibitory effect on fibroblasts153,154 and have been used post-

operatively to rescue failing filtering blebs, taking advantage of this effect of the drugs.155,156 While

very promising, the appropriate role for antiVEGF medications to augment trabeculectomy is being clarified.

Prior to the use of anti-VEGF drugs, most patients needing filtering surgery for NVG had glaucoma implant procedures, using the Ahmed, Baerveldt, Molteno, or Krupin valves (Fig. 11.13). Even so, long-term success rates were poor, with reported 5-year control of IOP in only 25–30% of patients with NVG.157,158 Progression of underlying ischemia can lead to vision loss even when IOP is well treated.159 Glaucoma implants can be placed either after or at the same time as pars plana vitrectomy and endophotocoagulation, with or without intravitreal bevacizumab. The tube can be placed

into the anterior chamber, or if the angle is closed into the sulcus, or through the pars plana.160–162

Placement of a glaucoma implant may be

technically difficult in an eye that has an encircling band. In these eyes, a drainage tube without a plate can be threaded from the anterior chamber into the

capsule that encases the scleral buckle (anterior chamber tube shunt to encircling band).163–165

As in trabeculectomy, there is an increased chance of success if the neovascular stimulus can be diminished before venting aqueous from the eye through a tube. Bevacizumab has been reported to be helpful in improving the outcome of glaucoma implant surgery as well. Two investigators have reported good results performing glaucoma implant

surgery after intravitreal injection of anti-VEGF medication.166,167 Eid reported a series of 20 eyes

in which he gave intravitreal bevacizumab, followed 1–2 weeks later by Ahmed glaucoma implant surgery. Successful IOP control was achieved in 85% of those who were treated with PRP and bevacizumab prior to glaucoma implant, compared to a 70% success rate in those who were given PRP alone. Again, more work remains to be done before the role of bevacizumab in glaucoma implant surgery for NVG.

In spite of the improving results being reported with trabeculectomy and glaucoma implant for NVG, in eyes that have a poor visual prognosis the risk of incisional surgery may not be justified. In such eyes, cyclophotocoagulation may be the most appropriate procedure. The diode laser, applied to the surface of the eye, can reduce IOP in

patients with NVG as effectively as can trabeculectomy (Fig. 11.14).168,169

Fig. 11.13 (a) Diagram of an Ahmed glaucoma implant with the drainage tube placed in the anterior chamber, covered by a patch graft of sclera, and ending in a reservoir sutured to the sclera allowing posterior

filtration. (b) Diagram of a Baerveldt glaucoma implant with the drainage tube placed through the pars plana into the vitreous cavity following vitrectomy and ending in a reservoir sutured to the sclera

Another way to ablate the ciliary body is the older technique of cyclocryotherapy, which tends to provoke more inflammation and pain

than does the diode laser. Also, diode laser energy may be delivered directly to the ciliary processes using the ocular endoscope. While