is well tolerated and may be useful in stabilizing or improving vision in young adults with subfoveal or juxtafoveal CNV secondary to idiopathic or inflammatory etiologies.36,37

SURGICAL THERAPY

Submacular surgery for myopic CNV has been evaluated in several small case series which showed that surgical removal of myopic CNV can result in improvement or stabilization of vision. However, post­ operative recurrence of CNV, RPE atrophy, and marked atrophic scar expansion lead to eventual visual decrease in many eyes following surgical removal of CNV, making this a less attractive option for the treatment of myopic CNV.38,39

The Submacular Surgery Trial (group H) was undertaken to evaluate the benefit of surgical therapy for idiopathic or POHS-related CNV.40 A successful outcome, defined as a final VA better than or no more than 7 letters worse than initial VA, was seen in 46% of eyes in the observation arm and 55% in the surgery arm. In the subgroup of eyes with VA worse than 20/100 at baseline, 76% of eyes in the surgery group versus 50% of eyes in the observation group had a successful outcome. Recurrent CNV developed in 58% of surgical eyes at 24 months. Retinal detachment developed in 4.5% of eyes in the surgery group, and 24% of initially phakic eyes in the surgery arm had cataract surgery during follow-up. Overall, this trial demonstrated no benefit or a smaller benefit to surgery than the trial was designed to detect, although the data indicate that surgery may be advantageous for patients with VA worse than 20/100.

Macular translocation surgery is another surgical therapy for CNV which involves repositioning the neurosensory retina overlying the CNV on to an area of healthier RPE and choriocapillaris. Preliminary experience with limited macular translocation has shown that this treatment modality offers the potential to improve vision in some eyes with subfoveal CNV secondary to myopia, POHS, angioid streaks, idiopathic neovascularization, and multifocal choroiditis. However, a high rate of retinal detachment was seen. Further studies are needed to define the precise role of macular translocation in the management of these conditions.41

ANTIANGIOGENIC THERAPY

The development of antiangiogenic therapies represented a major advance in the treatment of CNV. Ranibizumab (Lucentis, Genentech) is a specific affinity-matured, recombinant, humanized, anti-VEGF antigen-binding antibody fragment (Fab) that binds and neutralizes all the biologically active forms of VEGF-A. Ranibizumab was approved by the Food and Drug Administration (FDA) for the treatment of neovascular AMD after several large clinical trials demonstrated the safety and efficacy of intravitreal injections of ranibizumab for neovascular AMD. Ranibizumab therapy was the first treatment for neovascular AMD shown to improve vision for a significant number of patients.42 Bevacizumab (Avastin, Genentech) is a humanized, murine full-length antibody genetically modified from the same murine monoclonal antibody against VEGF as ranibizumab. Similar to ranibizumab, bevacizumab targets all the biologically active forms of VEGF-A. Bevacizumab is currently approved by the FDA for the treatment of metastatic colorectal cancer. Several case series have demonstrated the safety and efficacy of the off-label use of intravitreal bevacizumab for neovascular AMD.43,44 Based on encouraging results of ranibizumab and bevacizumab for the treatment of AMD-related CNV, these antiangiogenic therapies have also been used in the treatment of CNV attributable to causes other than AMD.

Several case series have demonstrated promising short-term results using intravitreal bevacizumab for the treatment of CNV in pathologic myopia. Yamamoto et al. reported a retrospective case series of 11 eyes with myopic subfoveal CNV treated with intravitreal bevacizumab.45 With a mean follow-up of 153 days, VAimproved by a mean of 3.5 lines, 8 of 11 eyes achieved 20/50 or better, and mean OCT central foveal thickness decreased by 103 m. Ruiz-Moreno et al. reported a prospective interventional study of bevacizumab for subfoveal and juxtafoveal

myopic CNV in 26 eyes.46 Patients were treated by three monthly injections with bevacizumab. Mean VA was 20/62 at baseline and 20/38 at month 6. Mean central foveal thickness was 282 m at baseline and 224 m at month 6. Leakage from CNV had ceased in all eyes at month 3, with closure of CNV lasting through month 6. No ocular or systemic safety issues were observed in either case series. These case series suggest that intravitreal bevacizumab is a safe and effective treatment for myopic CNV.

A retrospective case series has shown a benefit of intravitreal bevacizumab in patients with CNV associated with presumed ocular histoplasmosis.47 Twenty-eight eyes underwent intravitreal injection of bevacizumab for the treatment of CNV secondary to POHS. After a follow-up of 22 weeks, mean VA improved from a logMAR VA of 0.65 (Snellen equivalent 20/88) to a final logMAR VA of 0.43 (Snellen equivalent 20/54). Twenty eyes (71%) experienced an increase in VA, 4 eyes (14%) were unchanged, and 4 eyes (14%) experienced a decrease in vision. This series demonstrated that intravitreal bevacizumab may improve or stabilize VA in a majority of patients with neovascular complications of POHS.

The results of intravitreal bevacizumab for the management of CNV in patients with PXE-associated angioid streaks have also been evaluated in an interventional case series of 9 eyes.48 With a mean follow-up of 6 months, VA improved from a mean of 20/368 at baseline to 20/289 at the final visit. VA either improved or stabilized in all 9 eyes. OCT measurements decreased from a mean of 353 m at baseline to 201 m at the last visit. These short-term results support the use of intravitreal bevacizumab for the management of CNV in patients with angioid streaks.

Intravitreal bevacizumab has also been shown to be effective for idiopathic or inflammation-related CNV. Mandal et al. reported a prospective interventional case series of intravitreal bevacizumab in 32 eyes with idiopathic subfoveal CNV.49 At 12 weeks, mean VA improved from 20/133 to 20/50, and mean central macular thickness decreased from 314 to 236 m. At the final visit, 59% had a VA improvement of 3 lines or more, 34% remained stable, and 6% lost 3 lines or more. Adan et al. reported on the effects of intravitreal bevacizumab in 9 patients with inflammatory CNV.50 Bevacizumab injection resulted in CNV closure and a significant decrease in OCT thickness. VA improved in 8 eyes (88.8%) and remained stable in 1 eye (11.2%). No significant ocular or systemic adverse effects were observed in the reported series. These short-term results suggest that intravitreal bevacizumab is safe and effective in idiopathic and inflammatory CNV.

An ongoing multicenter open-label trial has been initiated to evaluate the safety and efficacy of ranibizumab in patients with CNV secondary to causes other than AMD (Heier, unpublished data). Patients are randomized to receive ranibizumab for either 12 monthly injections or three initial injections followed by additional injections administered for persistence or recurrence of CNV. Preliminary results of 20 patients with at least 1-month follow-up show that ranibizumab may be a promising treatment for non-AMD-related CNV. Ten of the 20 patients were randomized to receive 12 monthly injections, and 10 were randomized to receive 3 injections followed by pro re nata (PRN) dosing. In the first group, the mean change in VA compared with baseline was an improvement of 18.3 letters (n = 10) at 1 month and 24.3 letters (n = 3) at 6 months. OCT central retinal thickness decreased by a mean of 113 m at month 1 (n = 10) and 181 m at month 6 (n = 3). In the second group, VA improved by a mean of 4.6 letters at 1 month (n = 10) and 16.7 letters at 6 months (n = 3). OCT central retinal thickness improved by 129 m at month 1 (n = 10) and 215 m at month 6 (n = 5) (Figure 23.4). Continued follow-up is necessary to confirm the preliminary findings of the safety and efficacy of ranibizumab in non-AMD-related CNV.

SUMMARY AND KEY POINTS

●  CNV is a significant cause of vision loss in all age groups.

●  In patients younger than 50 years of age, CNV may occur as a secondary manifestation of various inherited and acquired conditions:

Pharmacotherapy to Amenable Diseases Retinal • 3 section

Myopia and Infection, Inflammation, to Secondary Neovascularization•Choroidal23 chapter

13.Vianna RN, Ozdal PC, Filho JP, et al. Longterm follow-up of patients with multifocal choroiditis and panuveitis. Acta Ophthalmol Scand 2004;82: 748–753.

14.Brown Jr J, Folk JC, Reddy CV, et al. Visual prognosis of multifocal choroiditis, punctate inner choroidopathy, and the diffuse subretinal fibrosis syndrome. Ophthalmology 1996;103:1100–1105.

15.Clarkson JG, Altman RD. Angioid streaks. Surv Ophthalmol 1982;26:235–246.

16.Shields JA, Federman JL, Tomer TL, et al. Angioid streaks. I. Ophthalmoscopic variations and diagnostic problems. Br J Ophthalmol 1975;59:257–266.

17.Deutman AF, Hoyng CB, van Lith-Verhoeven JJC. Macular dystrophies. In: Ryan SJ, editor. Retina, 4th edn. Philadelphia: Elsevier; 2006.

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18.Grossniklaus HE, Green WR. Choroidal neovascularization. Am J Ophthalmol 2004;137:496–503.

19.Ng EW, Adamis AP. Targeting angiogenesis, the underlying disorder in neovascular age-related macular degeneration. Can J Ophthalmol 2005;40:352–368.

20.Chan WM, Ohji M, Lai TY, et al. Choroidal neovascularisation in pathological myopia: an update in management. Br J Ophthalmol 2005;89:1522–1528.

21.Ciulla TA, Piper HC, Xiao M, et al. Presumed ocular histoplasmosis syndrome: update on epidemiology, pathogenesis, and photodynamic, antiangiogenic, and surgical therapies. Curr Opin Ophthalmol 2001;12:442–449.

22.Jalkh AE, Weiter JJ, Trempe CL, et al. Choroidal neovascularization in degenerative myopia: role of laser photocoagulation. Ophthalmic Surg 1987;18:721–725.

23.Secretan M, Kuhn D, Soubrane G, et al. Long-term visual outcome of choroidal neovascularization in pathologic myopia: natural history and laser treatment. Eur J Ophthalmol 1997;7:307–316.

24.Argon laser photocoagulation for neovascular maculopathy. Five-year results from randomized clinical trials. Macular Photocoagulation Study Group. Arch Ophthalmol 1991;109:1109–1114.

25.Laser photocoagulation for juxtafoveal choroidal neovascularization. Five-year results from randomized clinical trials. Macular Photocoagulation Study Group. Arch Ophthalmol 1994;112:500–509.

26.Krypton laser photocoagulation for idiopathic neovascular lesions. Results of

arandomized clinical trial. Macular Photocoagulation Study Group. Arch Ophthalmol 1990;108:832–837.

27.Lim JI, Bressler NM, Marsh MJ, et al. Laser treatment of choroidal neovascularization in patients with angioid streaks. Am J Ophthalmol 1993;116:414–423.

28.Pece A, Avanza P, Galli L, et al. Laser photocoagulation of choroidal neovascularization in angioid streaks. Retina 1997;17:12–16.

29.Regillo CD. Update on photodynamic therapy. Curr Opin Ophthalmol 2000;11:166–170.

30.Photodynamic therapy of subfoveal choroidal neovascularization in pathologic myopia with verteporfin. 1-year results of a randomized clinical trial – VIP report no. 1. Ophthalmology 2001;108:841–852.

31.Blinder KJ, Blumenkranz MS, Bressler NM, et al. Verteporfin therapy of subfoveal choroidal neovascularization in pathologic myopia: 2-year results of a randomized clinical trial – VIP report no. 3. Ophthalmology 2003;110:667–673.

32.Rosenfeld PJ, Saperstein DA, Bressler NM, et al. Photodynamic therapy with verteporfin in ocular histoplasmosis: uncontrolled, open-label 2-year study. Ophthalmology 2004;111:1725–1733.

33.Heimann H, Gelisken F, Wachtlin J, et al. Photodynamic therapy with verteporfin for choroidal neovascularization associated with angioid streaks. Graefes Arch Clin Exp Ophthalmol 2005;243:1115–1123.

34.Shaikh S, Ruby AJ, Williams GA. Photodynamic therapy using verteporfin for choroidal neovascularization in angioid streaks. Am J Ophthalmol 2003;135:1–6.

35.Browning AC, Amoaku WM, Chung AK, et al. Photodynamic therapy for angioid streaks. Ophthalmology 2007;114:1592.

36.Rogers AH, Duker JS, Nichols N, et al. Photodynamic therapy of idiopathic and inflammatory choroidal neovascularization in young adults. Ophthalmology 2003;110:1315–1320.

37.Wachtlin J, Heimann H, Behme T, et al. Long-term results after photodynamic therapy with verteporfin for choroidal neovascularizations secondary to inflammatory chorioretinal diseases. Graefes Arch Clin Exp Ophthalmol 2003;241:899–906.

38.Uemura A, Thomas MA. Subretinal surgery for choroidal neovascularization in patients with high myopia. Arch Ophthalmol 2000;118:344–350.

39.Ruiz-Moreno JM, de la Vega C. Surgical removal of subfoveal choroidal neovascularisation in highly myopic patients. Br J Ophthalmol 2001;85:1041–1043.

40.Hawkins BS, Bressler NM, Bressler SB, et al. Surgical removal vs observation for subfoveal choroidal neovascularization, either associated with the ocular histoplasmosis syndrome or idiopathic: I. Ophthalmic findings from a randomized clinical trial: Submacular Surgery Trials (SST) Group H Trial: SST report no. 9. Arch Ophthalmol 2004;122:1597–1611.

41.Fujii GY, Humayun MS, Pieramici DJ, et al. Initial experience of inferior limited macular translocation for subfoveal choroidal neovascularization resulting from causes other than age-related macular degeneration. Am J Ophthalmol 2001;131:90–100.

42.Rosenfeld PJ, Rich RM, Lalwani GA. Ranibizumab: phase III clinical trial results. Ophthalmol Clin North Am 2006;19:361–372.

43.Rich RM, Rosenfeld PJ, Puliafito CA, et al. Short-term safety and efficacy of intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration. Retina 2006;26:495–511.

44.Avery RL, Pieramici DJ, Rabena MD, et al. Intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration. Ophthalmology 2006;113:363–372 e5.

45.Yamamoto I, Rogers AH, Reichel E, et al. Intravitreal bevacizumab (Avastin) as treatment for subfoveal choroidal neovascularisation secondary to pathological myopia. Br J Ophthalmol 2007;91:157–160.

46.Ruiz-Moreno JM, Gomez-Ulla F, Montero JA, et al. Intravitreous bevacizumab to treat subfoveal choroidal neovascularization in highly myopic eyes: short-term results. Eye 2009 Feb;23(2):334–338.

47.Schadlu R, Blinder KJ, Shah GK, et al. Intravitreal bevacizumab for choroidal neovascularization in ocular histoplasmosis. Am J Ophthalmol 2008 May;145(5):875–878.

48.Bhatnagar P, Freund KB, Spaide RF, et al. Intravitreal bevacizumab for the management of choroidal neovascularization in pseudoxanthoma elasticum. Retina 2007;27:897–902.

49.Mandal S, Garg S, Venkatesh P, et al. Intravitreal bevacizumab for subfoveal idiopathic choroidal neovascularization. Arch Ophthalmol 2007;125:1487–1492.

50.Adan A, Mateo C, Navarro R, et al. Intravitreal bevacizumab (avastin) injection as primary treatment of inflammatory choroidal neovascularization. Retina 2007;27:1180–1186.

Pharmacotherapy to Amenable Diseases Retinal • 3 section

Endophthalmitis is characterized by marked inflammation of intraocular fluids and tissues. Severe visual loss may occur, even with prompt and appropriate diagnosis and treatment. Infective endophthalmitis may be categorized by the cause of the infection and the characteristic timing of clinical signs and symptoms.1 Categorization helps predict the underlying etiology and most likely causative organisms (Table 24.1).

The major category, representing over 70% of cases, is acute-onset, postoperative endophthalmitis, which is defined as endophthalmitis presenting within 6 weeks of intraocular surgery (Figure 24.1).1 Chronic postoperative endophthalmitis presents more than 6 weeks following intraocular surgery. Filtering bleb-associated endophthalmitis may present months or years following glaucoma filtering surgery.2 Post­ traumatic endophthalmitis occurs following open-globe injuries. Endogenous endophthalmitis occurs from hematogenous spread of systemic infection. Endophthalmitis may be associated with microbial keratitis3 and following office-based intravitreal injection.4

DISEASE INCIDENCE

The incidence of acute-onset postoperative endophthalmitis is in the range of 0.036–0.36% of eyes undergoing intraocular surgery.5–7 A 2005 survey of 15 920 cataract surgical procedures performed at the Bascom Palmer Eye Institute reported a risk of 0.04% following cataract surgery.8 An earlier survey reported rates of endophthalmitis of 0.2% following secondary intraocular lens (IOL) implantation, 0.2% after glaucoma surgery, and 0.03% after pars plana vitrectomy (PPV).9 In the USA, Medicare claims data suggest that the incidence of acute-onset post­ operative endophthalmitis may be increasing.10

The incidence of endophthalmitis following 20-gauge transscleral PPV was historically lower than that following other types of intra­ ocular surgery. However, the rate of endophthalmitis following smallgauge transconjunctival sutureless vitrectomy may be higher than that following 20-gauge PPV. Three recent retrospective series have reported an incidence of endophthalmitis following 25-gauge transconjunctival sutureless vitrectomy between 0.23% and 1.6%, as compared with an incidence following 20-gauge PPV of 0–0.03%.11–13

One series of open-globe injuries has reported an endophthalmitis rate of 6.8%.14

The incidence of endophthalmitis following intravitreal injections in prospective clinical trials is in the range of 1% per eye (Table 24.2).15–18 These reported rates relate to eyes, not to the number of total injections. In these trials, most eyes underwent a series of injections, so the incidence of endophthalmitis per injection is very low. For example, a recent report combining two large randomized clinical trials found an incidence of 0.05% per injection.19 The published rates of infection following intravitreal triamcinolone acetonide20 and bevacizumab21 (Avastin, Genentech, South San Francisco, CA) are generally in the range of 0.1% per injection or less. Recent large, retrospective case series of intravitreal injections of bevacizumab, ranibizumab (Lucentis, Genentech, South San Francisco, CA), and pegaptanib (Macugen, Eyetech, New York, NY) generally report infection rates in the range of 0.05% (Table 24.3).22

In acute-onset, postoperative endophthalmitis, preoperative risk factors include immune compromise (e.g., diabetes mellitus or immuno­ suppressive medications), chronic blepharitis, disease of the lacrimal drainage system, contaminated eye drops, contact lens wear, a contralateral ocular prosthesis, and active infection elsewhere in the body. Intraoperative risk factors include prolonged surgery, secondary IOL implantation, posterior capsular rupture, vitreous loss, iris prolapse, contaminated irrigating solutions or IOLs, and a slightly inferotemporal clear corneal incision. Postoperative risk factors include wound leaks and vitreous incarceration in the wound.

Some authors have suggested that clear cornea wounds are a risk factor for infection,23 but in a large series from the Bascom Palmer Eye Institute, the surgical technique (clear cornea phacoemulsification versus other methods) did not affect the incidence of endophthalmitis.8 In general, the clinical course, causative organisms, and visual outcomes from endophthalmitis following clear cornea cataract surgery are similar to those from other methods of cataract surgery.24

Using evidence-based medicine criteria, povidone-iodine antisepsis is the only technique to reach category II evidence for prevention of postoperative endophthalmitis.25

Risk factors for filtering bleb-associated endophthalmitis include a history of conjunctivitis, contaminated topical glaucoma medications, contact lenses, an inferior filtering bleb, bleb leak, bleb manipulations, and nasolacrimal duct obstruction.2 Risk factors for posttraumatic endophthalmitis include delayed primary repair (beyond 24 hours), soilassociated injuries, retained intraocular foreign bodies, and breach of lens capsule.14 Possible, but unproven, risk factors for endophthalmitis following 25-gauge transconjunctival sutureless vitrectomy include unsutured sclerotomy wounds, vitreous wick syndrome, early post­ operative hypotony, increasing use of adjuvants (such as intravitreal triamcinolone acetonide), and the reluctance of some surgeons to use subconjunctival antibiotics in these patients. Risk factors for endogenous endophthalmitis include debilitation, immune compromise, and intravenous drug abusers.26 Microbial keratitis is very infrequently associated with endophthalmitis, unless associated with corneal perforation.

The incidence of endophthalmitis following intravitreal injection can be reduced with a standardized protocol for aseptic injections, including the use of a sterile eyelid speculum and povidone-iodine.27 For example, in the VISION study, most endophthalmitis cases occurred in the setting of a protocol deviation.15 Prophylactic topical antibiotics are commonly used, although their efficacy is unproven.28

ETIOLOGY/PATHOGENESIS

The etiology of infective endophthalmitis is predicted by the clinical features and past history, and this is summarized in Table 24.1.29–33 Posttraumatic endophthalmitis is frequently caused by relatively more virulent organisms, such as Bacillus cereus.34

Endogenous endophthalmitis is more frequently caused by fungi, but bacterial cases may also occur.26 The most common causative organisms include Candida albicans and Aspergillus species. In bacterial

Pharmacotherapy to Amenable Diseases Retinal • 3 section