Summary for the Clinician

››Aqueous suppressants, beta-blockers, carbonic anhydrase inhibitors (topical and oral), and alpha adrenergics are the mainstay of treatment for the lowering of IOP in NVG.

››Oral acetazolamide and intravenous mannitol may be used with caution in the patient population due to a high prevalence of concomitant renal disease.

››Intense topical corticosteroids are recommended to quell the prominent inflammatory response in NVG.

››Topical atropine is also recommended for symptomatic relief and may decrease IOP and inflammation in NVG.

››Failure of medical therapy alone is the rule in advanced NVG.

49.2  What Is the Surgical Treatment of Choice for Neovascular Glaucoma? Should Everyone Always Get

a Tube Shunt to Control IOP, i.e., Can a Trabeculectomy Be Useful?

The three modalities most often employed when medical treatment fails to control IOP in NVG are tube shunts, trabeculectomy, and cycloablation. There is no role for laser trabeculoplasty in these highly abnormal angles. Almost 30 years ago, Simmons et al. attempted to actually coagulate the angle’s vessels, but produced vascular spasm and minimal long-term coagulation [9, 10].

Understanding the pathogenesis and disease course of NVG is vital to understanding the surgical choices and reasons for surgical failures. In the initial stages of NVG, fibrovascular tissue grows over the trabecular meshwork leading to decreased aqueous outflow and increased IOP. Next, myofibroblasts present in the neovascular tissue proliferate and contract, leading to progressive permanent angle-closure and progressive increase in IOP. Corneal endothelial proliferation can also extend over the angle [11]. When deciding upon the best surgical option for a patient who has failed medical therapy and when analyzing the surgical

literature, it is important to keep the above in mind and note that NVG is not a homogenous disease.

Surgical failure in NVG is usually defined as an inability to control IOP, as well as the development of phthisis and/or loss of light perception, regardless of the specific etiology of the latter. While phthisis and loss of light perception can occur from glaucomatous damage due to high IOP or as a complication of glaucoma surgery, progression of underlying ischemic disease, rather than failure to control IOP, is the most common cause of failure of surgeries for NVG [12]. It is therefore important to interpret study results in the context of the natural history of the underlying disease. The ideal surgical treatment is influenced by the underlying disorder as well as the clinical characteristics of each patient i.e., IOP, presence of active vs. regressed NV, prior laser or VEGF therapy, prior intraocular surgical therapies, degree of inflammation, degree of angle-closure, presence of hazy ocular media, and visual potential. Outcomes tend to be better in PDR compared to CRVOs [13], and ocular ischemic syndrome has the worst prognosis [3].

A majority of the literature concerning the surgical treatment of NVG consists of retrospective noncomparative case series [4]. Few comparative series and no prospective comparative studies or randomized trials exist in the literature (Tables 49.1 and 49.2). Comparing techniques in these different series is impossible due to different measures of successful outcome, differing and insufficient follow up times, and different baseline patient characteristics, including differences in etiology of NVG, baseline visual function, degree of NVA and PAS, and percentage of patients who have undergone pan-retinal photocoagulation (PRP). In many of these reports, all of these details are not even available.

Early studies with cyclocryoablation reported a large percentage of patients with vision loss and phthisis [35], relegating the use of cyclocryoablation and cyclophotocoagulation only to eyes with limited visual potential [4]. These early studies did not employ graduated cycloablation, which results in better outcomes [36, 37] and which some advocate as primary therapy in some cases even when there is good visual potential [3]. The bias towards using cycloablation only in eyes with poor visual potential, combined with the retrospective nature of studies in the literature has led to a reinforcement of the belief that cycloablation should only be used when visual prognosis is poor. Eid et al. found better outcomes with tube shunts

compared to cyclophotocoagulation in a retrospective study in which patients were matched in terms of underlying disease. However, in the cyclophotocoagulation group only 4.2% of patients had a visual acuity better than count fingers, while in the tube shunt group 41.7% of patients had vision better than count fingers. Additionally,­ a larger proportion of patients in the cyclophotocoagulation group had 360° of angleclosure [17], bringing the conclusions of this report into question. Currently, most glaucoma specialists recommend cyclophotocoagulation only in eyes with poor visual prognosis or when other methods have failed to control IOP. However, further studies are needed to evaluate the role of graduated cyclophotocoagulation in NVG, as some promising results have been published [37].

A study by Tsai et al. reporting poor long-term results of trabeculectomy with 5-FU in NVG – 5 year survival rate of filtering surgery with 5-FU was only 28% – is often cited as a rational for using tube shunts rather then trabeculectomy for NVG [11]. However these results are similar to long-term results with tube shunts (Tables 49.1 and 49.2) [13, 14]. The use of mitomycin C (MMC) may give superior results to 5-FU, though one small study found no difference between the two antimetabolites in NVG [38]. As mentioned above, failure of glaucoma surgery in NVG is most commonly caused by progression of underlying disease, and poor outcomes at 5 years likely represent this phenomenon rather than problems intrinsic to any one technique. In uninflammed NVG eyes treated with previous PRP, NVG becomes similar to

uncomplicated angle-closure and good results can be expected with trabeculectomy [29, 30]. That being said, younger eyes [11] and eyes with prior vitrectomy [27] tend to fare worse with trabeculectomy. The ability of anti-VEGF agents to induce rapid regression of NV of the angle and iris (discussed below) may lead to an expanded role for trabeculectomy in NVG.

As noted above, for many glaucoma specialists, tube shunts have become the treatment of choice for NVG. While trabeculectomy is a viable option in quiet eyes with regressed NV, tubes shunts seem to be a ­better

choice in inflamed eyes where failure rates of trabeculectomy are highest. While many advocate the use of one type of tube over others, the results with different devices are roughly equivalent [39] (see Table 49.1). As with trabeculectomy, tube shunt results are worse when used for NVG than for other types of glaucoma [40]. It is recommended that tube shunts be placed as far posterior as possible, i.e., at the pars plana in eyes that have undergone vitrectomy and in the sulcus in pseudophakic eyes. This will help to avoid corneal decompensation and blockage of tubes from neovascular membranes.

Summary for the Clinician

››Comparison of surgical techniques to treat NVG is severely limited due to a dearth of comparative and prospective studies as well as differing outcome measures and baseline patient characteristics in various studies.

››Though tube shunts are considered by many to be the surgical treatment of choice in NVG, trabeculectomy and tube shunts are likely equivalent in quiet eyes with regressed NV.

››Tubes shunts or cycloablation are more likely to be effective in inflamed eyes with active NV.

››Cycloablation is most often employed only in eyes with poor visual potential, but graduated cyclophotocoagulation may have a primary role in treatment of eyes with good visual potential, and its use should be further investigated.

››Over the long term, all surgical techniques share poor outcomes in NVG in large part due to progression of underlying disease.

49.3  How Should PRP and Glaucoma

Surgery Be Timed?

to control IOP to at least these levels (the mid 30s) is an indication for prompt glaucoma surgery. The clinician must also keep in mind that PRP can lead to a further increase in IOP [3], necessitating close follow-up in the interim period.

Recently Euswas and Warrasak published promising results in which PRP was delayed until at least 1 week after trabeculectomy with mitomycin-C because of hazy ocular media [25]. In their consecutive series of 21 patients and 23 eyes, they had a qualified success rate of 91.3% with follow-up of 12–47 months (mean 29 ± 11.3) [25].

Finally early data from the use of anti-VEGF agents indicate that their use may obviate the need to wait for PRP to take effect prior to glaucoma surgery, as discussed below.

Summary for the Clinician

››PRP should if possible, precede glaucoma surgery by 2–3 weeks to allow for regression of NV prior to surgical intervention, but this is often not possible due to hazy ocular media or significantly elevated IOP despite maximal medical management.

Determining the timing of PRP with relation to surgery must take into account the characteristics of the individual patient’s disease. Factors such as media opacities and significantly elevated IOP, despite maximal medical therapy, may lead to glaucoma surgery sooner than would otherwise be desired.

Ideally if given the luxury, PRP should be performed 2–3 weeks prior to filtering or tube implant surgery. This allows adequate time for the beneficial effects of PRP to take effect, including regression of iris and angle NV and a decrease in ocular inflammation, reducing the rates of intraoperative complications (hyphema) and early complications due to a prominent inflammatory response (such as bleb failure) [7, 12, 26, 29].

Eyes with previously healthy optic nerves likely can tolerate IOP in the mid 30s during this period after PRP. Already severely damaged optic nerves, from asymptomatic IOP elevation or from POAG for instance, may not be able to tolerate these same IOPs for 2–3 weeks without further significant optic neuropathy [7]. Inability

49.4  Is Bevacizumab Useful in Neovascular Glaucoma? What Kind of Results and Time-Course Can I Expect from Its Use? For NV of the Iris, Should It Be Injected into the Anterior Chamber

or Vitreal Cavity?

Multiple case reports /case series have been published showing promising results with the use of both intravitreal and intracameral bevacizumab (Figs. 49.1 and 49.2) in cases of iris NV and NVG secondary to PDR, CRVO, ocular ischemic syndrome, and radiation retinopathy [41–52] (Table 49.3). In the largest of these studies, Avery et al. studied the effects of intravitreal bevacizumab (6.25 mg–1.25 mg) on 45 eyes of 32 patients with iris or retinal NV from PDR. Of the 11 eyes with iris NV, 9 eyes (82%) showed complete regression of NV, while the remaining 2 eyes showed

Fig. 49.1  Bevacizumab prepared for intravitreal injection by the chemotherapy pharmacist

Fig. 49.2  A patient receiving intravitreal bevacizumab for neovascularization of the angle and iris due to proliferative diabetic retinopathy

only partial regression. Leakage on iris flourescein angiogram was noted to diminish in as little as 24 h. Recurrent leakage was seen as early as 2 weeks following injection and effects lasted up to the maximum

Table 49.3  Doses used for bevacizumab in neovascular glaucoma Anterior chamber dose

 1.25 mg/0.05 mL

 1.00 mg/ 0.04 mL Posterior segment dose

 1.25 mg/0.05 mL

follow-up time of 11 weeks in some eyes. Effects on IOP were not reported in this paper, nor were the number of eyes with NVG [43].

The largest consecutive case series looking at the use of bevacizumab specifically in NVG was reported by Iliev et al. (retinal vein occlusions) [47] and Gheith et al. (PDR and CRVOs) [45]. Both reviews included six consecutive patients who were given injections of 1.25 mg of intravitreal bevacizumab. In the study by Iliev et al., all cases showed marked regression of anterior segment NV and relief of symptoms within 48 h, while substantial lowering of IOP occurred in 3 of 6 eyes. Adjuvant cyclophotocoagulation was performed in the remaining 3, and subsequent PRP was performed in all eyes. The follow-up period was 4–16 weeks, and all patients had stable or improved vision, regression of angle and iris NV, and resolution of pain and anterior chamber inflammation at the end of follow-up [47].

In the study by Gheith et al. with a follow up period of 3–19 months (average 9.7 months), all cases showed complete regression of iris and angle NV with lowering of IOP at 1 week. Subsequent PRP was done at this time. Iris NV recurred in one case at 3 months and in a second case at 5 months. IOP was controlled with topical agents in cases without PAS, but subsequent glaucoma surgery (tube shunt or TMMC) was required to control IOP in patients with PAS [45]. Similar results were reported in the only published study in which intracameral bevacizumab was used [46]. These findings suggest that bevacizumab is most useful in NVG when given before PAS form and cause permanent damage to the aqueous outflow pathways. In all studies, no adverse effects were reported.

As discussed by the authors cited above, bevacizumab seems to be a promising adjunct to PRP in the treatment of NVG. The duration of action is unknown and it is likely that repeat injections would be required to control NVG when used as a sole agent. The transient effects of current anti-VEGF treatments make their use most promising as a temporizing measure until PRP results can take effect, or prior to glaucoma surgery.