AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

This disorder describes the growth of new blood vessels that originate from the choroid through a break in the Bruch membrane into the sub–retinal pigment epithelium (sub-RPE) or subretinal space. Choroidal neovascularization (CNV) is a major cause of visual loss.

Pathophysiology

Mechanisms of CNV are not understood. Virtually any pathologic process that involves the RPE and damages the Bruch membrane can be complicated by CNV. Recently, a protein derived from the RPE, pigment epithelium derived factor (PEDF), was found to have an inhibitory effect on ocular neovascularization. Another peptide, vascular endothelium growth factor (VEGF), is a well-known ocular angiogenic factor.

The balance between antiangiogenic factors (eg, PEDF) and angiogenic factors (eg, VEGF) is speculated to determine the growth of CNV. VEGF has been temporally and spatially correlated with the development of CNV. Histopathologic specimens obtained from submacular surgery reveal the presence of VEGF in CNV. In addition, several researchers have induced CNV formation in animal models by overexpressing VEGF. Once secreted, VEGF binds to its receptors in endothelial cells activating several signal transduction pathways that end with the formation of a network of new vessels. As new choroidal blood vessels grow, they may extend into the sub-RPE space (Gass type 1) or into the subretinal space (Gass type 2). The location, growth pattern, and type (1 or 2) of CNV depend on the patient's age and the underlying disease. Bleeding and exudation occur with further growth, accounting for the visual symptoms.

Frequency

United States

In the Wisconsin Beaver Dam Study, prevalence of CNV associated with age-related macular degeneration (ARMD) was 1.2% in adults aged 43-86 years. Myopia is the second most common cause of CNV in the United States and Europe. CNV is estimated to occur in 5-10% of myopes; 60-75% of these are subfoveal.

Disciform scars secondary to CNV from presumed ocular histoplasmosis syndrome (POHS) were present in 0.1% of people living in endemic areas. In multiple evanescent white dot syndrome (MEWDS), development of CNV is rare. In multifocal choroiditis, estimates of CNV range from 25-40% of patients. In punctate inner choroidopathy (PIC), 33% of patients develop CNV. Of these, 50% are subfoveal and result in visual acuities between 20/80 and 20/200.

CNV occurs in 5% of patients with birdshot chorioretinopathy. CNV occurs in virtually all choroidal ruptures during the healing phase; most involute spontaneously. In 15-30% of patients, CNV may recur and lead to a hemorrhagic or serous macular detachment with concomitant visual loss.

Mortality/Morbidity

• ARMD is the most common cause of visual loss in people older than 50 years in the developed world. Up to 90% of visual loss in ARMD is secondary to CNV.
  


• Myopia is the seventh greatest cause of registered blindness in the United States and Europe. CNV is responsible for most of this visual loss.
  


• POHS is an uncommon cause of visual loss. Incidence and prevalence in the blind of Tennessee, an area endemic for histoplasmosis, were reported to be 2.8% and 0.5%, respectively.

Sex

No gender predilection exists.

Certain diseases (ie, choroidal ruptures, angioid streaks, myopic macular degeneration, multifocal choroiditis, PIC, MEWDS) that may be complicated by CNV have gender proclivity.

Age

CNV is associated with multiple ocular conditions, so the age distribution of CNV reflects the underlying condition.  

• For instance, younger patients are affected with POHS, multifocal choroiditis, MEWDS, and PIC.
• Older patients will be affected by CNV secondary to ARMD.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• Painless loss of vision
• Metamorphopsia
• Paracentral or central scotoma
• Apparent change in image size

Physical

• Subretinal blood
• Subretinal fluid
• Lipid exudation
• Retinal pigment epithelial detachment
• Subretinal fibrosis (disciform scar)

Causes

Virtually any pathologic process that involves the RPE and damages the Bruch membrane can be complicated by CNV.

• Degenerative conditions
  
  
  • ARMD
  • Myopia
  • Angioid streaks
• Inflammatory or infectious conditions
  
  
  • Histoplasmosis
  • Sarcoidosis
  • Multifocal choroiditis
  • PIC
• Choroidal tumors
  
  
  • Nevi
  • Melanoma
  • Hemangioma
  • Osteoma
• Trauma
  
  
  • Choroidal rupture
  • Laser photocoagulation
• Idiopathic

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Lacquer crack with adjacent hemorrhage secondary to myopic macular degeneration
Atrophic macular scar with adjacent hemorrhage

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Laboratory studies may be indicated if certain underlying medical conditions, such as pseudoxanthoma elasticum (PXE), are present.

Imaging Studies

• Fluorescein angiography
  
  
  • Fluorescein angiography (FA) is an essential tool in diagnosing and managing CNV.
  • Several angiographic patterns have been described for CNV.
  • A lesion that hyperfluoresces in the early phases of the angiogram, maintains well-demarcated borders, and leaks late (obscuring its borders) is a classic CNV.
  • A lesion whose borders cannot be determined by FA is an occult CNV.
    
    
    • Fibrovascular pigment epithelial detachment (PED) and late leakage of undetermined source (LLUS) represent patterns of occult CNV.
    • A fibrovascular PED is a lesion that is elevated solidly and hyperfluoresces irregularly to different degrees.
    • The lesion may be well demarcated or poorly demarcated. LLUS is seen during FA as an irregular, indistinct, late, sub-RPE leakage.
  • According to its location relative to the center of the fovea, CNV has been classified as extrafoveal (200-1500 µm), juxtafoveal (1-199 µm), and subfoveal.
• Indocyanine green angiography
  
  
  • Indocyanine green (ICG) is a water-soluble tricarbocyanine dye that contains 5% sodium iodide; it rapidly binds almost completely to globulins after intravenous injection. ICG has a peak absorption and fluorescence in the near infrared range. This allows visualization of choroidal pathology through overlying serosanguineous fluid, pigment, or a thin layer of hemorrhage that usually blocks visualization during FA. Because ICG is bound tightly to the plasma proteins, less dye escapes from the choroidal circulation, allowing better definition of choroidal vasculature.
  • Three types of ICG patterns that are assumed to represent CNV may be imaged. A hot spot is a well-defined focal hyperfluorescent area that is less than one disc area in size. Hot spots usually fluoresce early. A plaque refers to a hyperfluorescent lesion that is larger than one disc area in size. A plaque usually does not fluoresce early, and its intensity diminishes late. Finally, some eyes harbor a combination of plaques and hot spots. In these eyes, the hot spots may be at the edge of the plaque, may overlie the plaque, or may be far from the plaque.
  • High-speed or dynamic ICG angiography uses a scanning laser ophthalmoscope that takes up to 32 frames per second. These images are recorded like a movie, and the flow in and out of the vessels can actually be seen. The main use of dynamic ICG angiography is in the identification of CNV feeder vessels that are located in the Sattler layer of the choroid.
• Optical coherence tomography
  
  
  • CNV causes thickening and fragmentation of the highly reflective RPE-choriocapillaris band. If the CNV is well defined, it is seen as a fusiform thickening of the RPE-choriocapillaris band. In contrast, poorly defined CNV is seen as a diffuse area of choroidal hyperreflectivity that blends into the normal contour of the normal RPE band. A normal boundary cannot be defined.
    
    
    • A subretinal hemorrhage is seen as a layer of moderate reflectivity that elevates the neurosensory retina and causes optical shadowing, resulting in a lower reflectivity of the underlying RPE and choroid. Serous, hemorrhagic, or fibrovascular RPE detachments reveal focal RPE elevations with shadowing of the structures beneath the elevated areas. Serous detachments are characterized by complete shadowing of the underlying structures. A hemorrhagic RPE detachment shows a moderately reflective layer beneath the detached RPE. Fibrovascular RPE detachments demonstrate moderate reflectivity throughout the entire sub-RPE space under the elevation.
    • Detachments of the neurosensory retina appear as elevations of a moderately reflective band above the RPE band. RPE tears can be seen as thick elevated areas of high reflectivity. The underlying choroid is completely shadowed, whereas the adjacent choroid reveals a hyperreflective image because of the absence of RPE. Retinal edema or thickness can be measured objectively by defining the anterior and posterior borders of the retina.
  • Rogers and coworkers have proposed an optical coherence tomography (OCT) classification scheme of CNV following photodynamic therapy (PDT).³⁰
    
    
    • Stage I occurs shortly after PDT and lasts for about a week. It is characterized by an inflammatory reaction that causes an increase in intraretinal fluid in a circular fashion that corresponds with the treatment spot.
    • Stage II represents the restoration of a near-normal foveal contour with diminished subretinal fluid occurring 1-4 weeks after treatment.
    • Stage III represents reperfusion and involution of CNV. It typically occurs 4-12 weeks following treatment and is subdivided into 2 categories based on the ratio of subretinal fibrosis to fluid present. Stage IIIa contains a greater subretinal fluid to fibrosis ratio, indicating active CNV. Lesions in Stage IIIb have more prominent fibrosis with minimal intraretinal fluid, indicating inactive CNV.
    • Further involution of CNV may lead to cystoid macular edema, signifying Stage IV.
    • In Stage V, CNV and the subretinal fluid resolve, leading to fibrosis and retinal thinning.
  • Despite the many advantages of OCT, FA remains the imaging modality of choice in the management of CNV. Currently, OCT cannot replace FA in the management of CNV.

Histologic Findings

New capillaries and fibroblasts originate from the choroid and grow through a defect in the Bruch membrane into the subretinal space (type 2 CNV) or the sub-RPE space (type 1 CNV). Reactive hyperplastic RPE is present at the advancing edge of CNV.

Specimens obtained from surgical excision of CNV reveal that the most common cellular components are vascular endothelium and RPE. These were present in more than 85% of samples. Fibrocytes and macrophages also have been identified in more than 50% of specimens. Extracellular components include collagen and fibrin. VEGF has been identified in the specimens obtained during submacular surgery.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Current knowledge of molecular events in the pathogenesis of CNV has allowed CNV to be targeted with very specific antiangiogenic factors. Targeting VEGF allows a two-hit strategy: antiangiogenesis and antipermeability. VEGF is 50,000 times more potent than histamine in inducing vascular permeability. An important component of decreased vision is the accumulation of subretinal fluid secondary to increased vascular permeability.

• Pegaptanib sodium
  
  
  • Pegaptanib sodium is an aptamer against VEGF165, the isoform identified with pathological angiogenesis. An aptamer is an oligonucleotide that acts like a high affinity antibody to VEGF, neutralizing it before it can contact its receptor.
  • Pegaptanib sodium is given as an intravitreal injection every 6 weeks.
  • Overall, pegaptanib sodium was able to decrease visual loss when compared to placebo in a similar fashion to that of PDT therapy with verteporfin. Only 6% of eyes were reported to have an improvement in visual acuity of 3 or more lines after 12 months of follow-up. Unlike therapy with verteporfin, all eyes with exudative ARMD benefited from treatment regardless of lesion composition. In addition, the trials using pegaptanib sodium included eyes with larger lesions than those eyes in the trials using verteporfin.
  • Complications associated with the intravitreal injection of pegaptanib sodium are few but include retinal detachment and endophthalmitis.
• Ranibizumab
  
  
  • Ranibizumab is a recombinant monoclonal antibody Fab fragment that neutralizes all active forms of VEGF-A.
  • Ranibizumab is delivered as a monthly intravitreal injection.
  • The US Food and Drug Administration approved the use of ranibizumab for the treatment of all angiographic subtypes of subfoveal neovascular ARMD.
  • Intravitreal ranibizumab is the first treatment that significantly improves visual acuity in up to 40% of eyes.
  • Although infrequent, complications associated with this treatment include endophthalmitis and severe uveitis.
• Bevacizumab
  
  
  • Bevacizumab is a humanized, recombinant monoclonal immunoglobulin G (IgG) antibody that binds and inhibits all VEGF isoforms and is currently approved for systemic use in metastatic colorectal cancer and non–small cell lung cancer.
  • Off-label use of intravitreal bevacizumab for CNV secondary to ARMD was first reported in 2005. Most of the reports of bevacizumab are uncontrolled, open-label case series that have proven functional and anatomical efficacy, short-term safety, and low cost.
  • Results from several studies suggest that bevacizumab may be useful in the treatment of CNV secondary to myopia, angioid streaks, and ARMD.
• Several other antiangiogenic compounds are currently in different stages of development. These agents include angiostatic steroids, such as anecortave acetate, squalamine, genetic therapy with an adenovector of PEDF, si (small interference) RNA-VEGF, and combretastatin A4.

Surgical Care

• The Macular Photocoagulation Study (MPS) proved the efficacy of laser photocoagulation in the treatment of CNV secondary to ARMD, POHS, and idiopathic causes.
• The goal is to completely obliterate CNV.
• Partial treatment of CNV is not beneficial when compared to observation.
  
  
  • Extrapolate these results to other conditions that are complicated by CNV on a case-by-case basis. Many patients and their physicians choose not to elect immediate loss or several lines of vision in an attempt to have a very modest visual improvement in 18 months.
  • Extrapolation of MPS results to CNV secondary to myopia probably is not indicated in juxtafoveal CNV.
  • Cases of enlargement of laser scars through the fovea with subsequent visual loss have been reported.
• PDT uses light-activated drugs and nonthermal light to achieve selective destruction of CNV with minimal effects on the surrounding normal tissues.
  
  
  • Randomized clinical trials have shown that PDT with verteporfin is effective in reducing visual loss in certain eyes with CNV secondary to ARMD.
  • In eyes with at least some classic CNV, treatment with verteporfin reduced visual loss. Subgroup analysis revealed that eyes with a classic component of greater than 50% fared much better than those eyes with a classic component of less than 50%. In eyes with a classic component of less than 50%, no difference existed in visual loss between the eyes treated with placebo and the eyes treated with verteporfin.
  • Another study reported that therapy with verteporfin for occult CNV secondary to ARMD was effective in slowing the progression of visual loss. However, such benefit was only seen after the second year of follow-up. Subgroup analysis revealed that eyes with a visual acuity of 20/50 or worse or eyes with lesions smaller than 4 disc areas in size had a better outcome. Further analysis of the data revealed that lesion size rather than lesion composition is a strong predictor of visual benefit following PDT with verteporfin.
  • Despite all the encouraging initial results, PDT provides marginal benefit. Most eyes will continue losing vision, though at a slower rate, and only 15% of eyes will manifest some visual improvement.
  • PDT in combination with intravitreal triamcinolone, bevacizumab, or ranibizumab may have better visual outcomes than PDT alone in patients with ARMD.
• High-speed ICG confocal angiography guided laser photocoagulation of feeder vessels is reportedly beneficial in selected patients with exudative ARMD but remains unproven.
• Uncontrolled studies have recommended surgical excision of subfoveal CNV via pars plana vitrectomy. The goal is to remove CNV but to leave the underlying RPE and choriocapillaris intact.
  
  
  • Surgical excision of type 2 CNV would be more beneficial than type 1 CNV.
  • Pilot studies resulted in substantial numbers of patients with worse vision, many with unchanged vision, and a small number with apparent improved vision. The current rhetoric is that stabilization may occur with surgery.
  • The Submacular Surgery Trial (SST), a randomized multicenter prospective trial sponsored by the National Eye Institute (NEI), confirmed that submacular surgery in eyes with CNV secondary to ARMD generally does not have a good visual outcome. In addition, with CNV secondary to idiopathic causes and POHS, submacular surgery offers a modest benefit in eyes with a baseline visual acuity of 20/100 or worse.
• Two surgical methods to translocate the fovea have been developed to treat subfoveal CNV. The previously subfoveal CNV is now juxtafoveal or extrafoveal; then, standard laser photocoagulation or PDT can be performed without damaging the fovea. Caution is warranted because high rates of retinal detachment, proliferative vitreoretinopathy (PVR), macular holes, recurrent CNV, cystoid macular edema (CME), and hemorrhage have been reported.
• Low-dose radiation therapy has been effective in inhibiting neovascularization in different tissues.
  
  
  • A randomized clinical trial reported better visual outcomes in eyes with exudative ARMD receiving radiation therapy of 24 Gy given in 6 fractions of 4 Gy each compared to observation.
  • However, other trials do not support radiation therapy as a treatment alternative in eyes with CNV secondary to ARMD. Long-term effects are unknown, and radiation retinopathy is definitely a concern.

Consultations

Diagnosis and treatment is often difficult. Consider referring to a retinal specialist who is experienced with these conditions.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Drug Category: Anti-VEGF therapy

Reduces risk of visual loss similar to that seen with PDT.

Drug Category: Photosensitizers for photodynamic therapy

Reduction of leakage from abnormal, neovascular vessels, resulting in reduced visual loss.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

• Two weeks following laser photocoagulation, a patient should be observed and have a fluorescein angiogram.
  
  
  • Pay special attention to the borders, especially the foveal border, of the laser treatment zone to detect any persistence.
  • If no leakage is detected, the patient should have another fluorescein angiogram 4 weeks later or if there are new changes on the Amsler grid.
  • If no leakage is detected again, another angiogram should possibly be obtained 4-6 weeks later.
• Clinical examination cannot replace FA during the first 18 months after laser treatment, because most persistent and recurrent leakage occurs during this period.

Complications

• After 5 years of follow-up study, the MPS reported that 55% of patients with exudative ARMD, 33% of patients with POHS, and 34% of patients with idiopathic CNV had a recurrent or persistent CNV after laser photocoagulation.
• • These recurrences, regardless of etiology, tended to be toward the foveal side and were associated with visual loss.
  • In most cases, photocoagulation of these recurrent CNV is indicated.
  • Laser treatment of peripapillary CNV may be complicated by thermal damage to the papillomacular bundle.
• Surgical excision of CNV may be complicated by retinal detachment, postvitrectomy cataract, choroidal hemorrhage, epimacular membrane, and macular hole.
• • CNV recurrence following excision occurred in up to 44% of cases.
  • How to effectively manage these recurrences is unclear.

Prognosis

• Location, growth pattern, type (1 or 2) of CNV, and underlying condition determines the prognosis.
• • The 5-year follow-up of the MPS ARMD study showed that 46% of eyes with extrafoveal CNV that were photocoagulated had severe visual loss (loss of 6 lines or more from baseline) compared to 42% of eyes that were followed. In the juxtafoveal study, 49% of treated eyes compared to 58% of observed eyes had severe visual loss. In the subfoveal study, 22% of treated eyes and 47% of observed eyes had severe visual loss.
  • The 5-year follow-up of the MPS POHS study has shown that 12% of eyes with extrafoveal CNV that were photocoagulated had severe visual loss compared to 42% of eyes that were followed.
    • In the juxtafoveal study, 12% of treated eyes also had severe visual loss compared to 28% of eyes that were followed.

    • The natural history of untreated subfoveal CNV secondary to POHS shows that 14-23% of patients retain 20/40 or better visual acuity.

    • Pilot studies of photocoagulation of subfoveal CNV secondary to POHS were inconclusive.

    • Photocoagulation of peripapillary CNV secondary to POHS reduced severe visual loss from 26% of control eyes to 14% of treated eyes.
  • The 5-year follow-up of the MPS idiopathic CNV study showed that 27% of eyes with extrafoveal CNV that were photocoagulated had severe visual loss compared to 44% of eyes that were followed.
    • Few eyes were entered in the juxtafoveal study; at the 3-year follow-up, 10% of treated eyes versus 27% of observed eyes had severe visual loss.

    • The natural history for idiopathic subfoveal CNV is not necessarily associated with profound loss of vision.

    • Size of CNV seemed to be an important prognostic factor. If the CNV was smaller than 1 disc area at initial examination, prognosis was better.

    • In the MPS, the median visual acuity for untreated extrafoveal and juxtafoveal idiopathic CNV was 20/80.
  • CNV in myopia does not necessarily imply bad prognosis.
    • Up to 50% of patients can expect spontaneous improvement or stabilization of vision.
    • About 25% of extrafoveal CNV becomes subfoveal, but up to 25% of subfoveal CNV involutes spontaneously.

Patient Education

• Once diagnosed with maculopathy secondary to POHS, the patient is asked to self-monitor each eye with a near card and an Amsler grid.
• If a disturbance is detected, prompt examination is encouraged.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Early detection and treatment may help to reduce the chance of visual loss.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

1. Blinder KJ, Blumenkranz MS, Bressler NM, Bressler SB, Donato G, Lewis H, et al. Verteporfin therapy of subfoveal choroidal neovascularization in pathologic myopia: 2-year results of a randomized clinical trial--VIP report no. 3. Ophthalmology. Apr 2003;110(4):667-73. [Medline].
2. Blinder KJ, Bradley S, Bressler NM, Bressler SB, Donati G, Hao Y. Effect of lesion size, visual acuity, and lesion composition on visual acuity change with and without verteporfin therapy for choroidal neovascularization secondary to age-related macular degeneration: TAP and VIP report no. 1. Am J Ophthalmol. Sep 2003;136(3):407-18. [Medline].
3. Bressler NM, Bressler SB, Childs AL, Haller JA, Hawkins BS, Lewis H, et al. Surgery for hemorrhagic choroidal neovascular lesions of age-related macular degeneration: ophthalmic findings: SST report no. 13. Ophthalmology. Nov 2004;111(11):1993-2006. [Medline].
4. Bressler NM, Bressler SB, Gragoudas ES. Clinical characteristics of choroidal neovascular membranes. Arch Ophthalmol. Feb 1987;105(2):209-13. [Medline].
5. Bressler SB, Bressler NM, Fine SL, Hillis A, Murphy RP, Olk RJ, et al. Natural course of choroidal neovascular membranes within the foveal avascular zone in senile macular degeneration. Am J Ophthalmol. Feb 1982;93(2):157-63. [Medline].
6. Chakravarthy U, Houston RF, Archer DB. Treatment of age-related subfoveal neovascular membranes by teletherapy: a pilot study. Br J Ophthalmol. May 1993;77(5):265-73. [Medline].
7. Dawson DW, Volpert OV, Gillis P, Crawford SE, Xu H, Benedict W, et al. Pigment epithelium-derived factor: a potent inhibitor of angiogenesis. Science. Jul 9 1999;285(5425):245-8. [Medline].
8. de Juan E Jr, Loewenstein A, Bressler NM, Alexander J. Translocation of the retina for management of subfoveal choroidal neovascularization II: a preliminary report in humans. Am J Ophthalmol. May 1998;125(5):635-46. [Medline].
9. Emerson MV, Lauer AK, Flaxel CJ, Wilson DJ, Francis PJ, Stout JT, et al. Intravitreal bevacizumab (Avastin) treatment of neovascular age-related macular degeneration. Retina. Apr-May 2007;27(4):439-44. [Medline].
10. Eyetech Study Group. Anti-vascular endothelial growth factor therapy for subfoveal choroidal neovascularization secondary to age-related macular degeneration: phase II study results. Ophthalmology. May 2003;110(5):979-86. [Medline].
11. Ferris FL 3rd, Fine SL, Hyman L. Age-related macular degeneration and blindness due to neovascular maculopathy. Arch Ophthalmol. Nov 1984;102(11):1640-2. [Medline].
12. Folk JC, Reddy CV. White dot chorioretinal inflammatory syndromes. In: Medical and Surgical Retina Advances, Controversies, and Management. 1994;385-399.
13. Fuller B, Gitter KA. Traumatic choroidal rupture with late serous detachment of macula. Report of successful argon laser treatment. Arch Ophthalmol. Apr 1973;89(4):354-5. [Medline].
14. Goff MJ, Johnson RN, McDonald HR, Ai E, Jumper JM, Fu A. Intravitreal bevacizumab for previously treated choroidal neovascularization from age-related macular degeneration. Retina. Apr-May 2007;27(4):432-8. [Medline].
15. Gragoudas ES, Adamis AP, Cunningham ET, Feinsod M, Guyer DR. Pegaptanib for neovascular age-related macular degeneration. N Engl J Med. Dec 30 2004;351(27):2805-16. [Medline].
16. Gross JG, King LP, de Juan E Jr, Powers T. Subfoveal neovascular membrane removal in patients with traumatic choroidal rupture. Ophthalmology. Apr 1996;103(4):579-85. [Medline].
17. Grossniklaus HE, Green WR. Histopathologic and ultrastructural findings of surgically excised choroidal neovascularization. Submacular Surgery Trials Research Group. Arch Ophthalmol. Jun 1998;116(6):745-9. [Medline].
18. Hawkins BS, Bressler NM, Bressler SB, Davidorf FH, Hoskins JC, Marsh MJ, 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. Nov 2004;122(11):1597-611. [Medline].
19. Hawkins BS, Bressler NM, Miskala PH, Bressler SB, Holekamp NM, Marsh MJ, et al. Surgery for subfoveal choroidal neovascularization in age-related macular degeneration: ophthalmic findings: SST report no. 11. Ophthalmology. Nov 2004;111(11):1967-80. [Medline].
20. Ho AC, Yannuzzi LA, Pisicano K, DeRosa J. The natural history of idiopathic subfoveal choroidal neovascularization. Ophthalmology. May 1995;102(5):782-9. [Medline].
21. Klein R, Klein BE, Linton KL. Prevalence of age-related maculopathy. The Beaver Dam Eye Study. Ophthalmology. Jun 1992;99(6):933-43. [Medline].
22. Lambert HM, Capone A Jr, Aaberg TM, Sternberg P Jr, Mandell BA, Lopez PF. Surgical excision of subfoveal neovascular membranes in age-related macular degeneration. Am J Ophthalmol. Mar 15 1992;113(3):257-62. [Medline].
23. Laud K, Spaide RF, Freund KB, Slakter J, Klancnik JM Jr. Treatment of choroidal neovascularization in pathologic myopia with intravitreal bevacizumab. Retina. Oct 2006;26(8):960-3. [Medline].
24. Lazic R, Gabric N. Verteporfin therapy and intravitreal bevacizumab combined and alone in choroidal neovascularization due to age-related macular degeneration. Ophthalmology. Jun 2007;114(6):1179-85. [Medline].
25. Machemer R, Steinhorst UH. Retinal separation, retinotomy, and macular relocation: II. A surgical approach for age-related macular degeneration?. Graefes Arch Clin Exp Ophthalmol. Nov 1993;231(11):635-41. [Medline].
26. Macular Photocoagulation Study Group. Argon laser photocoagulation for neovascular maculopathy. Five-year results from randomized clinical trials. Arch Ophthalmol. Aug 1991;109(8):1109-14. [Medline].
27. Macular Photocoagulation Study Group. Laser photocoagulation for juxtafoveal choroidal neovascularization. Five-year results from randomized clinical trials. Arch Ophthalmol. Apr 1994;112(4):500-9. [Medline].
28. Pharmacological Therapy for Macular Degeneration Study Group. Interferon alfa-2a is ineffective for patients with choroidal neovascularization secondary to age-related macular degeneration. Results of a prospective randomized placebo-controlled clinical trial. Pharmacological Therapy for Macular Degeneration Study Group. Arch Ophthalmol. Jul 1997;115(7):865-72. [Medline].
29. Photodynamic Therapy Study Group. Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: one-year results of 2 randomized clinical trials--TAP report. Arch Ophthalmol. Oct 1999;117(10):1329-45. [Medline].
30. Rogers AH, Martidis A, Greenberg PB, Puliafito CA. Optical coherence tomography findings following photodynamic therapy of choroidal neovascularization. Am J Ophthalmol. Oct 2002;134(4):566-76. [Medline].
31. Rosenfeld PJ. Intravitreal avastin: the low cost alternative to lucentis?. Am J Ophthalmol. Jul 2006;142(1):141-3. [Medline].
32. Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK, Chung CY, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. Oct 5 2006;355(14):1419-31. [Medline].
33. Rosenfeld PJ, Moshfeghi AA, Puliafito CA. Optical coherence tomography findings after an intravitreal injection of bevacizumab (avastin) for neovascular age-related macular degeneration. Ophthalmic Surg Lasers Imaging. Jul-Aug 2005;36(4):331-5. [Medline].
34. Rosenfeld PJ, Rich RM, Lalwani GA. Ranibizumab: Phase III clinical trial results. Ophthalmol Clin North Am. Sep 2006;19(3):361-72. [Medline].
35. Roth DB, Downie AA, Charles ST. Visual results after submacular surgery for neovascularization in age-related macular degeneration. Ophthalmic Surg Lasers. Nov 1997;28(11):920-5. [Medline].
36. Schmidt-Erfurth U, Miller J, Sickenberg M, Bunse A, Laqua H, Gragoudas E, et al. Photodynamic therapy of subfoveal choroidal neovascularization: clinical and angiographic examples. Graefes Arch Clin Exp Ophthalmol. May 1998;236(5):365-74. [Medline].
37. Sears J, Capone A Jr, Aaberg T Sr, Lewis H, Grossniklaus H, Sternberg P Jr, et al. Surgical management of subfoveal neovascularization in children. Ophthalmology. May 1999;106(5):920-4. [Medline].
38. Shiraga F, Ojima Y, Matsuo T, Takasu I, Matsuo N. Feeder vessel photocoagulation of subfoveal choroidal neovascularization secondary to age-related macular degeneration. Ophthalmology. Apr 1998;105(4):662-9. [Medline].
39. Sivagnanavel V, Evans JR, Ockrim Z, Chong V. Radiotherapy for neovascular age-related macular degeneration. Cochrane Database Syst Rev. 2004;(4):CD004004. [Medline].
40. Spaide RF, Guyer DR, McCormick B, Yannuzzi LA, Burke K, Mendelsohn M, et al. External beam radiation therapy for choroidal neovascularization. Ophthalmology. Jan 1998;105(1):24-30. [Medline].
41. Spaide RF, Laud K, Fine HF, Klancnik JM, Meyerle CB, Yannuzzi LA, et al. Intravitreal bevacizumab treatment of choroidal neovascularization secondary to age-related macular degeneration. Retina. Apr 2006;26(4):383-90. [Medline].
42. Spaide RF, Sorenson J, Maranan L. Photodynamic therapy with verteporfin combined with intravitreal injection of triamcinolone acetonide for choroidal neovascularization. Ophthalmology. Feb 2005;112(2):301-4. [Medline].
43. Staurenghi G, Orzalesi N, La Capria A, Aschero M. Laser treatment of feeder vessels in subfoveal choroidal neovascular membranes: a revisitation using dynamic indocyanine green angiography. Ophthalmology. Dec 1998;105(12):2297-305. [Medline].
44. Steen B, Sejersen S, Berglin L, Seregard S, Kvanta A. Matrix metalloproteinases and metalloproteinase inhibitors in choroidal neovascular membranes. Invest Ophthalmol Vis Sci. Oct 1998;39(11):2194-200. [Medline].
45. Sternberg P Jr, Lewis H. Photodynamic therapy for age-related macular degeneration: a candid appraisal. Am J Ophthalmol. Mar 2004;137(3):483-5. [Medline].
46. Teixeira A, Moraes N, Farah ME, Bonomo PP. Choroidal neovascularization treated with intravitreal injection of bevacizumab (Avastin) in angioid streaks. Acta Ophthalmol Scand. Dec 2006;84(6):835-6. [Medline].
47. Tewari A, Dhalla MS, Apte RS. Intravitreal bevacizumab for treatment of choroidal neovascularization in pathologic myopia. Retina. Nov-Dec 2006;26(9):1093-4. [Medline].
48. Thomas MA, Dickinson JD, Melberg NS, Ibanez HE, Dhaliwal RS. Visual results after surgical removal of subfoveal choroidal neovascular membranes. Ophthalmology. Aug 1994;101(8):1384-96. [Medline].
49. Verteporfin Roundtable Participants. Guidelines for using verteporfin (visudyne) in photodynamic therapy for choroidal neovascularization due to age-related macular degeneration and other causes: update. Retina. February/March 2005;25(2):119-134. [Medline].
50. Wood CM, Richardson J. Chorioretinal neovascular membranes complicating contusional eye injuries with indirect choroidal ruptures. Br J Ophthalmol. Feb 1990;74(2):93-6. [Medline].
51. Wormald R, Evans J, Smeeth L, Henshaw K. Photodynamic therapy for neovascular age-related macular degeneration. Cochrane Database Syst Rev. 2003;(2):CD002030. [Medline].
52. Wu L, Murphy RP. Photodynamic therapy: a new approach to the treatment of choroidal neovascularization secondary to age-related macular degeneration. Curr Opin Ophthalmol. Jun 1999;10(3):217-20. [Medline].
53. Wyhinny GJ, Jackson JL, Jampol LM, Caro NC. Subretinal neovascularization following multiple evanescent white-dot syndrome. Arch Ophthalmol. Oct 1990;108(10):1384-5. [Medline].
54. Yamamoto I, Rogers AH, Reichel E, Yates PA, Duker JS. Intravitreal bevacizumab (Avastin) as treatment for subfoveal choroidal neovascularisation secondary to pathological myopia. Br J Ophthalmol. Feb 2007;91(2):157-60. Epub 2006 Jul 26. [Medline].

Article Last Updated: Jul 25, 2007