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Core Messages

Rubeotic glaucoma is a late manifestation of ischemic retinal disease

In the early form the chamber angle is open; later stages present with angle closure

Panretinal photocoagulation and cryotherapy are indicated to reduce retinal ischemia

Pars plana vitrectomy and endolaser coagulation in combination with silicone oil endotam-

ponade may have an additional effect on ischemia

Transscleral cyclophotocoagulation is indicated for advanced cases or drainage implants Retinectomy can create a posterior outflow for aqueous

Anti-VEGF and steroid injections are under investigation

17.1 Definition and Classification

In most cases (97 %) neovascular glaucoma is caused by ischemia [5]. The most common underlying diseases are proliferative diabetic retinopathy and proliferative retinopathy after central retinal vein occlusion (CRVO). Rare types of neovascular glaucoma are of non-ischemic nature (e.g., tumor-induced, inflammatory disease) but should be separated because of different treatment strategies (Table 17.1).

Neovascular glaucoma due to retinal ischemia can be separated into three different forms:

Early neovascular glaucoma with open angle Late neovascular glaucoma with closed angle Absolute glaucoma with or without painful blind eye (Fig. 17.1a–c)

Table 17.1. Underlying diseases causing neovascular glaucoma

17.2 Prognosis

Rubeotic secondary glaucoma has to be considered as a late manifestation of a progressive underlying ischemic retinal disease. In most cases visual acuity is markedly reduced caused by retinal and optic disk changes (e.g., macular edema, optic atrophy) and only secondarily by glaucomatous optic neuropathy.

Clinical-pathological examination of enucleated eyes demonstrated that secondary angle closure glaucoma accounts for 40 – 60 % of all enucleated glaucoma eyes [12, 32]. The most common type of glaucoma was neovascular glaucoma. Rubeosis iridis was seen in nearly half of all enucleated glaucoma eyes.

17.3 Treatment

The treatment strategy depends on the stage of neovascular glaucoma (Fig. 17.2).

The aims of treatment are:

Treatment of retinal ischemia

Regression of rubeosis iridis and angle neovascularization

Avoidance of irreversible secondary angle closure by peripheral anterior synechiae (PAS)

Control of intraocular pressure Maintenance of visual acuity

17.3.1Early Rubeotic Secondary Glaucoma (Open Angle Type)

Early rubeotic secondary glaucoma is characterized by neovascularization of the angle but the absence or only the beginning of peripheral anterior synechiae (Figs. 17.1a, b, 17.3a).

It is important to recognize that new vessels are able to grow in the angle without slit-lamp evidence of iris neovascularization (Fig. 17.4). Browning et al. [7] found angle neovascularization without iris neovascularization in 12 % of eyes with CRVO. The CRVO study reported about 10 % of eyes with nonischemic CRVO and 6 % of eyes with ischemic CRVO with angle neovascularization without iris neovascularization [4]. Similar observations have been described in patients with diabetes mellitus [6]. Gonioscopically fine irregular vessels that may overgrow the trabecular meshwork can be seen. There is no general recommendation of how often gonioscopy should be performed.

Treatment of retinal ischemia is the most important step to resolve iris and angle neovascularization and remains the most important factor for intraocular pressure (IOP) regulation in early (open-angle) rubeotic glaucoma. In patients with clear optic media, panretinal photocoagulation (PRP) is performed. Ohnishi et al. [34] documented regression of rubeosis in 68 % of patients and normalization of IOP in 42 % of patients treated with PRP.

Transient IOP increase can be treated with topical drugs reducing aqueous humor production (betablockers, carboanhydrase inhibitors, 2-analogues). Prostaglandin analogues probably are less effective

276 II General Concepts in the Diagnosis and Treatment of Retinal Vascular Disease

Retinectomy + silicone oil tamponade

or failure removal of silicon oil +

pars plana drainage device

Fig. 17.2. Therapeutic guidelines for the treatment of neovascular glaucoma (PRP panretinal photocoagulation, PPV pars plana vitrectomy, CPC cyclophotocoagulation, TE+MMC trabeculectomy with mitomycin C)

c

Fig. 17.3c. Siderosis of the angle

Fig. 17.4. Advanced rubeosis iridis with neovacularization of the angle in an eye with proliferative diabetic retinopathy

in glaucoma eyes associated with intraocular inflammation and should be avoided.

Rubeosis is always associated with an incomplete blood-aqueous humor-barrier leading to a persistent high level of serum proteins and cells within the anterior segment of the eye. This inflammatory trigger is one important mechanism in the induction and progression of peripheral anterior synechiae. Rimexolone, a high-potent steroid derivate with a reduced IOP – increasing risk compared to other topical steroids, can be used to reduce this inflammatory reaction.

When adequate PRP (1,200 – 1,600 laser spots) is not completely achievable, other modalities should be considered and added, including panretinal cryotherapy or transscleral diode laser retinopexy. Panretinal cryotherapy is effective in causing regression of rubeosis. Sihota et al. [40] achieved IOP control in 82 % of patients at 1 year after panretinal cryotherapy.

In recent years, pars plana vitrectomy and lensectomy (if necessary) with endolaser photocoagulation have developed into the most appropriate therapeutic option in patients with proliferative ischemic retinopathy and progression of rubeosis and reti-

endothelial growth factor (VEGF) is maintained within the vitreous cavity after vitrectomy in proliferative diabetic retinopathy, and probably in other ischemic retinopathies as well [19]. Therefore vitrectomy without endotamponade is probably insufficient for the control of progressive ischemic retinopathy with manifest rubeotic glaucoma. Antiproliferative surgery including pars plana vitrectomy, endolaser coagulation of the retina and ciliary body combined with silicone oil endotamponade is necessary. Bartz-Schmidt et al. [3] reported normalization of IOP in 72 % of patients with uncontrolled rubeotic glaucoma associated with proliferative diabetic retinopathy or central retinal vein occlusion [3]. Silicon oil tamponade prevents postoperative complications and supports regression of rubeosis by separating the anterior from the posterior segment.

Persistent IOP elevation with open angle or limited anterior synechiae after regression of rubeosis can be treated with all antiglaucomatous drugs except pilocarpine. Pilocarpine may enhance the disruption of the blood-aqueous humor barrier and the formation of posterior synechiae.

In refractory cases, trabeculectomy may be performed in patients without previous vitrectomy. However, trabeculectomy without antimetabolites has shown a worse outcome in neovascular glaucoma. Mietz et al. [28] reported a failure rate of 80 % in this group of patients. Therefore trabeculectomy is now recommended in association with the primary use of antimetabolites. Despite this modification, the failure rate of filtration surgery is still high. Hyang and Kim [18] reported a success rate of 29 % in patients with neovascular glaucoma 12 months after trabeculectomy with mitomycin C. Mandal et al. [25] observed a surgical success rate of 67 % in 15 eyes with neovascular glaucoma and a follow-up between 2 and 82 months.

After failure of trabeculectomy, translimbal implantation of drainage devices (Molteno, Baerveldt, Ahmed) or transscleral cyclophotocoagulation can be performed. The classical translimbal implantation is an appropriate method in eyes with only a partially occluded angle. Mermoud and colleagues [27] reported the success of single-plate Molteno implantation in 60 eyes with neovascular glaucoma. The success rate was 62 % at 1 year, but decreased to 10 % at 5 years. Loss of light perception was seen in 48 % and progression to phthisis bulbi occurred in 18 %. The authors concluded that Molteno implanta-

tion may be used for pain relief and avoidance of enucleation.

Alternatively, transscleral cyclophotocoagulation can be successfully used, especially in older patients 17 II (see Sect. 17.3.2). One study from Taiwan reported comparable results of diode laser cyclophotocoagulation and trabeculectomy in patients with neovascular glaucoma [23]. Another study compared the results of tube-shunt surgery versus noncontact Nd:YAG cyclophotocoagulation [13]. In this study satisfactory control of IOP was achieved in 37 % of eyes treated with noncontact cyclophotocoagulation compared to 67 % receiving a tube shunt surgery.

Using contact cyclophotocoagulation more patients can be controlled satisfactorily (see Sect. 17.3.2).

17.3.2Advanced Rubeotic Secondary Glaucoma (Angle Closure Type)

Late rubeotic secondary glaucoma is characterized by complete closure of the angle due to excessive peripheral anterior synechiae (Figs. 17.1c, 17.3b). Typical biomicroscopic visible changes of the anterior segment of the eye include corneal changes (epithelial edema, band keratopathy, peripheral neovascularization), strong rubeosis and covering of the iris by a fibrovascular membrane leading to pupil distortion, ectopium uveae, heterochromia due to siderosis after repeated intraocular bleeding (Fig. 17.5), posterior synechiae and often cataract.

In the presence of secondary angle closure, IOP often remains increased despite control of the ischemic retina and regression of iris neovascularization. Topical antiglaucomatous therapy is mostly insufficient. Only aqueous humor-reducing drugs may reduce the IOP, because the angle is closed by fibrovascular membranes.

In the presence of an active ischemic retina, cyclophotocoagulation (endoor transscleral) is often necessary in combination with pars plana vitrectomy, endolaser photocoagulation and silicone oil tamponade.

Using contact diode laser transscleral cyclophotocoagulation different success rates have been reported in the literature ranging from 56 % to 87 % within 1 – 3 years of follow-up [33, 36]. There may be an increased risk of hypotonia and phthisis compared to other types of glaucoma [29].

Transscleral diode laser cyclophotocoagulation is the treatment of choice in patients with long-term intravitreal silicone oil tamponade. Sivagnavel et al. [41] reported an overall success rate of 50 %. Some patients developed hypotonia despite intravitreal silicone oil. Han et al. [17] achieved complete success in 55 % of their patients with silicone oil tamponade after retinal detachment. Another aspect is whether repeated vitrectomies or later removal of the silicone oil may increase the risk of hypotonia after cyclophotocoagulation. Nabili and Kirkness [31] reported five out of ten eyes with diabetic neovascular glaucoma and previous repeated vitrectomies developed hypotonia after diode laser cyclophotocoagulation.

Even after repeated cyclophotocoagulation, an elevated IOP is seen in a substantial number of eyes with secondary angle glaucoma. Therefore, alternative strategies are needed. Relatively new treatment options are pars-plana-modified drainage implants

(Baerveldt implant, Ahmed glaucoma valve) (Fig. 17.6). In 2000 and 2002 the first clinical reports were published concerning the efficacy of a pars plana modified Baerveldt implant with a Hofmann elbow [8, 24]. The studies reported a high success rate (> 90 %) in a relatively small group of eyes. One study directly compared the efficacy of Nd:YAG cyclopho-

tocoagulation and pars plana modified Baerveldt implant in neovascular glaucoma [8]. After 6 months of follow-up, the success rate for cyclophotocoagulation was 77 % and for Baerveldt implantation it was 95 %. The modified Ahmed glaucoma valve with pars plana clip is another drainage device with resisted

Fig. 17.6. Pars-plana-modified Baerfeld implant with Hofmann elbow

flow. IOP regulation without further antiglaucomatous therapy (complete success) was reported in 64 % of patients with secondary angle closure glaucoma 1 year after surgery [37]. So far little is known about

the long-term efficacy of these implants. II 17 Another option is retinectomy, which opens a new

posterior outflow path for the aqueous to the absorbing choroid (Fig. 17.7). In 2003, long term results 5 years after surgery (retinectomy with intraocular gas tamponade) were reported [22]. Nearly 53 % of all treated eyes showed a long term regulated IOP. On the other hand, 48 % of eyes developed retinal complications. The high risk of complications may be reduced by primarily used silicone oil tamponade.

17.3.3Blind Painful Eye with Rubeotic Secondary Glaucoma

The primary aim of treatment of a painful blind eye is an eye free of complaints accompanied by a cosmetically acceptable situation (Fig. 17.8). There is no clear therapeutic guideline concerning the treatment of a painful blind eye with (neovascular) glaucoma. Three different causes of pain should be considered:

Pain due to an increased intraocular pressure Pain due to ciliary body spasm in persistent intraocular inflammation

Pain due to ocular surface diseases

Concerning the high intraocular pressure in a blind painful eye, medical treatment is rarely successful. Intraocular surgery should be avoided because of the (low) risk of sympathetic ophthalmia [14]. Transscleral cyclophotocoagulation may be effective in the reduction of intraocular pressure and pain resolution [36]. Martin and Broadway [25] reported a success rate (resolution of pain) of 95 % after diode laser cyclophotocoagulation [26]. Successful treat-

Fig. 17.7. Retinectomy in the temperosuperior quadrant of the retina

Fig. 17.8. Blind painful eye with advanced rubeotic glaucoma after multiple anterior and posterior segment surgery. Band keratopathy, peripheral corneal neovascularization; endothelial precipitates are visible

ment was associated with a reduction of IOP of more than 30 % of the initial value.

Alternatively, retrobulbar injection of alcohol or chlorpromazine can be performed or may be added 17 II in patients after failure of cyclophotocoagulation. Chen et al. [9] reported a successful treatment using 1 – 2 ml chlorpromazine (25 mg/ml) in 80 % of 20 patients. More than 50 % of these patients were free

of pain for more than 1 year.

Enucleation remains the ultima ratio, but will resolve the pain in the overwhelming majority of patients (90 %) [10, 39]. Especially in cases of low intraocular pressure and beginning phthisis associated with pain, enucleation resolves the pain and may contribute to a better cosmetic situation.

Inflammation-induced pain should be treated with anti-inflammatory agents. Topical corticosteroids of high potency (dexamethasone, prednisolone) in combination with cycloplegics may resolve pain in eyes with active non-infectious intraocular inflammation. Seldomly non-infectious scleritis may occur and should be treated with oral corticosteroids for several weeks.

Pain due to disturbances of the ocular surface including dry eye, decompensation of the cornea, band keratopathy or trophic corneal ulceration may complicate the situation in a blind eye. In some cases pain can be resolved by artificial tears, therapeutic contact lens, or removal of band keratopathy. Sometimes treatment of trophic corneal changes by amnion membrane transplantation or covering with conjunctiva may be necessary [38].

17.3.4Treatment Options Under Investigation

There is no doubt that new treatment strategies are needed to improve the long term prognosis of rubeotic secondary glaucoma and retain a useful vision over many years.

The first major aim of new therapeutic procedures is the regression and control of neovascularization/rubeosis. Several antiangiogenic substances are under evaluation. Intravitreal injection of triamcinolone acetonide may result in a regression of rubeosis and was also reported to reduce the intraocular pressure in patients with neovascular glaucoma due to diabetic retinopathy and ischemic central retinal vein occlusion [20]. The question is whether triamcinolone may be used as an additional tool in the treatment of neovascular glaucoma. There is a substantial risk of a further increase of intraocular pressure in glaucoma eyes, so the risk-benefit ratio in a single patient cannot be calculated [21].

The high angioproliferative potency of vascular endothelial growth factor (VEGF) resulting in iris

neovascularization and neovascular glaucoma has been demonstrated by a range of experimental and clinical studies [42, 43]. Now, anti-VEGF therapy (pegaptanib) seems to be effective in the treatment of neovascular age-related macular degeneration [16]. The potency of pegaptanib on iris neovascularization should be evaluated in future studies.

A further area of research is gene therapy. Experimental studies demonstrated that ocular angiogenesis can be inhibited by an adenovirus carrying the human von Hippel-Lindau tumor-suppressor gene [1]. VEGF expression was significantly reduced after intraocular gene transfer in a monkey model.

Squalamine, an antiangiogenic aminosterol, inhibited iris neovascularization after systemic injection in a primate model [15]. A further potentially useful agent may be anecortave, a synthetic derivate of cortisol. Specific chemical modifications to the cortisol structure have resulted in the creation of a potent inhibitor of blood vessel growth. First comparative studies using anecortave as a posterior juxtascleral depot reported a regression of subfoveal choroidal neovascularization in age-related macular degeneration within 12 months [2, 11]. At present no data are known about the possible additive effect of anecortave in the treatment of proliferative retinopathies and iris neovascularization/neovascular glaucoma.

Finally, Muller et al. [30] reported the possible treatment of iris neovascularization with photodynamic therapy with verteporfin [30].

The second major aspect includes procedures that may allow an early effective control of the intraocular pressure in manifest rubeotic (secondary angle closure) glaucoma decreasing the risk of overtreatment and phthisis. At present different treatments (cyclophotocoagulation, drainage devices, retinectomy) are used for the same situation. One important step is to compare these different procedures by prospective, randomized, multicenter trials. In addition, other new surgical ideas are being introduced.

Suprachoroidal seton implantation (a modified Krupin eye valve) has been reported to allow the drainage of aqueous humor from the anterior chamber to the suprachoroidal space [35]. Several patients with painful blind eyes due to neovascular glaucoma in proliferative diabetic retinopathy were successfully treated. This new treatment option should be proven in a larger patient group under well designed study conditions.