Choroidal Neovascular Membranes

Back

Background

Choroidal neovascular membrane (CNVM) is an abnormal vascular network originating in the choroid and breaching Bruch’s membrane into the sub-retinal pigment epithelium (sub-RPE), subretinal, or intraretinal space.[1]  CNVM arise most commonly from retinal conditions such as neovascular age-related macular degeneration (AMD), polypoidal choroidal vasculopathy (PCV), myopic macular degeneration, central serous chorioretinopathy, macular telangiectasia, presumed ocular histoplasmosis syndrome (POHS) and other inflammatory chorioretinopathies, trauma, and angioid streaks. However, CNVMs may be idiopathic. CNVMs may result in visual disturbance, especially if there is exudation or hemorrhage from the CNVM.[1, 2, 3, 4, 5, 6, 7, 8, 9, 10]

Pathophysiology

The retina is a multilayered tissue composed of neurons specialized in visual information processing. Photons of light traverse the entire thickness of the retina where they are received by the deepest (ie, outermost) retinal layer, comprised of photoreceptors. Photoreceptors convert photons of light into electrical impulses, which then are transmitted back inward through the retinal layers until reaching the inner layers comprised of ganglion cells, the axons of which comprise the innermost retinal layer, the nerve fiber layer (NFL). The NFL axons converge at the optic disc, where they continue onward towards the visual pathways of the brain.[11, 12, 13, 14, 15, 16, 17]

Beyond the photoreceptor layer lies the retinal pigment epithelium (RPE), a layer of epithelial cells that nourishes and maintains the overlying neurosensory retina, especially the photoreceptors. The RPE also functions as the outer blood-retinal barrier, preventing molecules >300kDa from passing into or out of the retina under physiologic conditions. In pathologic states such as CNVM, this barrier is disrupted, and due to the apical-to-apical arrangement of photoreceptors and RPE, fluid or hemorrhage may accumulate in the subretinal potential space. Bruch’s membrane separates the RPE from the highly vascular choroid and is comprised of 5 layers: RPE basement membrane, inner collagenous layer, elastin layer, outer collagenous layer, and basement membrane of the choriocapillaris.[11, 16, 17, 18]  

CNVM occurs due to disruption in Bruch’s membrane which allow neovascular tufts to extend underneath the RPE (sub-RPE, ie, Type 1 CNVM). Because Type 1 CNVM is sub-RPE and thus not in contact with the overlying neurosensory retina, visual symptoms can be mild unless there is exudation, ie, leakage of fluid or hemorrhage into the subretinal or retinal spaces.[1, 17]  In Type 2 CNVM, the neovascular membrane breeches the RPE and extends in the potential space between the neurosensory retina and RPE (ie, subretinal space).[1, 17]  The pathophysiology of Type 3 CNVM, also known as retinal angiomatous proliferation (RAP), is not fully understood but may involve the development of intraretinal neovascularization as well as subretinal and choroidal neovascularization, leading ultimately to retino-choroidal anastomosis between these.[1, 17, 19, 20]  CNVMs arising from wet AMD is more likely to Type 1 than are CNVMs from other causes.[21, 22]

Exudation from CNVMs may result in hemorrhage or fluid accumulating in the retina, subretinal, or sub-RPE spaces, resulting in impairment or damage to neurosensory retina and in turn, visual symptoms. Existing pharmacologic treatments of CNVM therefore center largely upon resolving exudation, as evidenced by resolution of fluid and/or hemorrhage on examination and imaging. Rarely, hemorrhage may break through the retina resulting in vitreous hemorrhage. Over time, CNVM may progress to a cicatricial stage with formation of disciform scars, resulting in destruction of the RPE and overlying outer retina over time.[1, 17, 21, 22]

Epidemiology

There are no large studies evaluating the epidemiology of CNVM specifically, as CNVM is a sequela of a multitude of retinal diseases.[1, 2, 3, 4, 5, 6, 7, 8, 9, 10]  Thus, existing epidemiological studies focus upon the incidence of causative conditions for CNVM themselves. 

The most common cause of CNVM is neovascular AMD.[1]  In the United States, the prevalence of AMD (non-neovascular and neovascular AMD) is estimated to be 2% amongst patients aged 40-44 years, and the prevalence rises with age for those aged 45-49 (5.4%), 50-54 (7.8%), 55-59 (9.7%), 60-64 (11.5%), 65-69 (13.3%), 70-74 (18%), 75-79 (24%), 80-84 (32.4%), and 85-89 (42.2%) years. Approximately 10% of patients with AMD have neovascular AMD. Rates of AMD and neovascular AMD are higher amongst women than men and higher amongst those of European ancestry than amongst those of Asian or African ancestry. Other risk factors for neovascular AMD include smoking and genetic risk alleles.[23, 24]  PCV is a variant of AMD that is more common in patients of African or Asian descent than those of European descent.[2]

Mortality/Morbidity

CNVM and most related diseases are not characterized by increased mortality rates. Morbidity is limited to the loss of central vision; the peripheral vision is virtually always retained in cases of CNVM except in rare cases.

Prognosis

Early diagnosis and immediate intervention are crucial to improving outcomes. The prognosis of all CNVMs is very good, especially if treatment is initiated before bleeding or scarring occurs. Many patients with CNVM, especially due to etiologies such as AMD, may require treatment for many years.

Patient Education

Teaching patients to use the Amsler grid, reading text and other home testing schemes daily, is essential to improving outcomes. Patients should be instructed to contact their eye physician immediately if any visual disturbance occurs. Office staff should be instructed that these patients should be seen within a few days and undergo OCT imaging and clinical examination.

History

Patients with choroidal neovascular membranes (CNVMs) may report the following:

Or less commonly, the following:

In some cases, especially with Type 1 CNVM without exudation, the patient may notice no visual disturbance.[1, 2, 3, 4, 5, 6, 7, 8, 9, 10]

Physical

Causes

CNVM arise most commonly from retinal conditions such as neovascular age-related macular degeneration (AMD), polypoidal choroidal vasculopathy (PCV, myopic macular degeneration, central serous chorioretinopathy, macular telangiectasia, presumed ocular histoplasmosis syndrome (POHS) and other inflammatory chorioretinopathies, trauma, and angioid streaks. However, CNVMs may also be idiopathic.[1, 2, 3, 4, 5, 6, 7, 8, 9, 10]  

The clinician will perform an examination using a slit lamp biomicroscopy and a fundus contact lens or 78-or 90-diopter (D) lens. Optical coherence tomography (OCT) is standard-of-care for assessing the retinal microstructure to identify and characterize the CNVM. Fluorescein angiography (FA), indocyanine green angiography (ICG), and/or OCT-angiography are required in some cases.

Clinical findings

CNVM typically appear as gray or greenish lesions and may occur in the macula or in the periphery. There may be secondary subretinal or intraretinal fluid or hemorrhage. Other clinical findings may be present which provide clues as to the etiology of the CNVM, such as: drusen and RPE changes (AMD), peripapillary atrophy, tilted nerve, staphyloma or myopic fundus (myopic degeneration), inflammatory uveitic lesions, choroidal rupture, angioid streaks, etc.[1, 2, 3, 4, 5, 6, 7, 8, 9, 10]  

Ocular imaging findings

OCT has become an essential imaging tool for the diagnosis of CNVM and its causes and complications, as well as evaluation of response to treatment. Fluorescein angiography (FA), indocyanine green angiography (ICG), and/or OCT-angiography (OCT-A) may be needed in some cases to diagnose CNVM and/or its causes, as well as to help guide treatments such as laser or photodynamic therapy (PDT) when indicated.[25, 26, 27, 28, 29, 30]

Typical findings of CNVM on OCT include highly reflective fibrovascular tissue with irregular borders between RPE and Bruch’s membrane (Type 1 CNVM) or above the RPE (Type 2 CNVM), or as a serous fibrovascular pigment epithelial detachment (PED). Type 3 CNVM manifests with sub-RPE hyperreflective tissue with intraretinal angiomatous changes and cystic changes. In the setting of exudation from CNVM, there may be intraretinal or subretinal fluid, visualized as cystic hyporeflective spaces within or under the retina, respectively, or hemorrhage visualized as mildly hyperreflective material underneath or within the retinal tissues. Late-stage cicatricial CNVM, ie, disciform scar, manifests with hyperreflective dense tissue with overlying atrophy of the outer retinal tissues.[28, 31, 32, 33]   

FA features of CNVM include early hyperfluorescence with leakage characterized by increased hyperfluorescence with poorly defined edges in late stages for Type 2 CNVM. A lacy neovascular net may be noted. Type 1 CNVM often manifests with ill-defined, poorly demarcated hyperfluorescence or late leakage on FA. On ICG, CNVM show low-intensity hypercyanescence. ICG may be useful for highlighting Type 1 CNVMs in cases where FA is inconclusive. Retino-choroidal vascular communications may be visible on early phases of ICG.[34, 35, 36, 37, 38]  On OCT-A, CNVM is visualized as a neovascular, higher flow, complex.[39, 40, 41]

PCV is a variant of AMD characterized by Type 1 CNVM with polypoid lesions and branching networks with feeder and draining vessels. FA may show features of Type 1 CNVM noted above, but typically is not ideal for diagnosing PCV. ICG is helpful for PCV because it demonstrates early hypercyanescence demonstrating branching vascular networks, with or without associated polypoid lesions. Rarely, pulsations may be noted in the polypoid lesions during early ICG phases. Features on OCT that suggest a PCV diagnosis rather than AMD include: sharp-peaked (inverted U-shaped) PED, en face OCT with complex RPE elevation, and ring-like lesion in the subretinal space (consistent with a polyp). Other features include presence of SRF more commonly than of intraretinal fluid. The PED may be notched such that a sharp-peaked PED is connected to a lower-lying PED. The polyps may be visualized under the sharp-peaked PED, whereas a double-layer sign signifying the branching vascular network may be seen in the low-lying PED. OCT-A demonstrates the branching vascular networks under the RPE and polyps.[2, 42, 43, 44, 45, 46]

Laboratory Studies

No laboratory tests exist for most diseases associated with choroidal neovascular membranes (CNVMs).

Hereditary macular degeneration usually can be identified from clinical presentation, family history, angiography, electroretinogram (ERG),[42]  electro-oculogram (EOG),[43]  psychophysical testing (eg, color vision, perimetry, dark adaptation), and genetic testing.

The diagnosis of histoplasmosis is based on fundus findings not serologic or skin testing.

Angioid streaks usually are due to pseudoxanthoma elasticum (PXE), but they also have been reported in patients with sickle cell disease and Paget disease.

Histologic Findings

CNVM is a clinical and ocular-imaging-based diagnosis, and tissue diagnosis is not indicated.

Medical Care

Zinc/antioxidant therapy

In the Age-Related Eye Disease Study (AREDS and AREDS2), zinc combined with other antioxidants has been shown to reduce the progression rate of AMD to advanced stages such as wet AMD with CNVM, by approximately 25% in patients with intermediate stage AMD. No benefit has been demonstrated in eyes without AMD or early AMD.[47, 48, 49, 50, 51]

Intravitreal injection

The standard treatment for most cases of CNVM includes intravitreal injection of anti-vascular endothelial growth factor (VEGF) medications. Upregulation of VEGF has been implicated in the pathogenesis of CNVM development and vascular permeability in CNVM leading to exudation.[52, 53, 54]  

Most Phase II and III trials for medications for CNVM focus on wet AMD. There are limited studies in myopic CNVM. For all other indications for CNVM, smaller studies have demonstrated efficacy, and anti-VEGF agents are used off-label. Below is a summary of major trials for intravitreal injection therapies for CNVM with wet AMD.

Pegaptanib (Macugen, Bausch and Lomb) was the first anti-VEGF agent approved for wet AMD. Pegatabnib blocked VEGFA-165. Since then, a variety of anti-VEGF agents have been demonstrated to be more effective at safely improving vision by promoting resolution of exudation from and regression of CNVMs.[55, 56]  

Bevacizumab 1.25mg (Avastin) is an off-label; full-length, humanized, recombinant monoclonal antibody against all isoforms of VEGF-A which was initially used off-label and found to promote resolution of exudation, regression of CNVM, and improvement in vision in patients with wet AMD.[57, 58]

Ranibizumab 0.5mg (Lucentis, Genentech) is FDA approved for wet AMD and myopic CNVM. Ranibizumab is a humanized, monoclonal antibody fragment against all isoforms of VEGFA. The ANCHOR and MARINA clinical trials established efficacy and safety of monthly intravitreal ranibizumab as compared to sham (MARINA) or PDT (ANCHOR) for minimally classic/occult CNVM (MARINA) or classic CNVM (ANCHOR). In the MARINA trials 95% of patients treated with ranibizumab, versus 62% of sham, lost fewer than 3 lines of vision; and 34% of ranibizumab-treated patients gained more than 3 lines of vision (versus 5% of sham-treated patients). On average, ranibizumab-treated patients gained 7 letters of vision at 24 months, as compared to 10 letters lost in the sham-treated patients. The ANCHOR study reported similar findings.[59, 60]  

The HARBOR study compared monthly versus monthly as needed (PRN) intravitreal ranibizumab injection therapy in patients with wet AMD and found similar results at 24 months, with the PRN group achieving a mean gain of 7.9 letters with an average of 13.3 injections over 2 years (versus 24 injections in the monthly group).[61]  However, significant clinical trial and real world data suggests that patients who receive more injections achieve superior visual outcomes and significant under treatment exists in clinical practice.[62, 63, 64]  For example, the SEVEN-UP trial demonstrated that 7 years after ANCHOR or MARINA, 43% had stable or improved vision compared to the baseline upon entry into the ANCHOR/MARINA trials, while 34% had 3 or more lines of vision loss. In the 3.4 year interval of the SEVEN-UP study, eyes had a mean of 6.8 injections, but the subgroup of eyes who received 11 or more injections had significantly better vision gains. In addition, while 68% of eyes in the study had active exudation from wet AMD, only 46% were receiving ongoing injections.[63]  

There is a lack of consensus on appropriate treatment regimens for wet AMD, with retinal physicians employing monthly or bi-monthly injections at fixed intervals, monthly as-needed injections in which an examination and imaging are performed monthly and injection given if there is active exudation, and/or treat-and-extend regimen. The treat-and-extend regimen aims to balance the need to limit treatment burden with the data demonstrating that undertreatment and persistent exudation are associated with worse long-term vision. In a treat-and-extend regimen, after one or more loading monthly intravitreal injections for wet AMD, the interval between injections is slowly extended by typically 2 weeks while the retina remains dry. If recurrent fluid is noted, the interval is reduced until resolution of exudation is achieved. The optimal treatment interval is identified and maintained for a period of time and then possibly extended again in the future. If patients achieve an every 12 week or longer regimen for a period of time (eg, 1 year) without exudative activity, some clinicians will stop treatment and monitor closely for re-activation.[65]

The CATT trial was a multicenter, single-blinded, randomized, controlled trial comparing bevacizumab monthly, bevacizumab monthly as needed, ranibizumab monthly, and ranibizumab monthly as needed for wet AMD. Patients in the monthly as needed groups were evaluated every month to determine whether treatment was indicated at that visit. At 2 years, the CATT trial found similar visual outcomes with bevacizumab versus ranibizumab. Of note, monthly treatment resulted in slightly better visual outcomes than monthly as needed treatment.[64]

Aflibercept 2mg (Eylea, Regeneron) and aflibercept 8mg (Eylea HD, Regeneron) are FDA approved for wet AMD. It is a recombinant fusion protein from human VEGF-receptor1/2 that targets VEGFA, VEGFB ,and platelet-derived growth factor (PGF). The VIEW1/2 clinical trials demonstrated that aflibercept 2mg monthly or every 2 months (after 3 initial monthly doses) was non-inferior to monthly ranibizumab for treatment of wet AMD.[66]   In the PULSAR study, patients received 3 monthly aflibercept high dose (8mg) injections followed by treatment at q8-16 weeks (with more frequent retreatment as needed based on clinical evaluation). These studies found that 78% of patients maintained treatment intervals of 12 or more weeks over the 2 year study period. Eyes treated with aflibercept 8mg at these extended intervals achieved noninferior vision gains as compared to aflibercept 2mg given every 8 weeks, with fewer injections over 2 years (mean 8.2-9.7 injections versus 2.8 injections).[67]

Brolucizumab 6mg (Beovu, Novartis) is a single-chain antibody fragment that inhibits VEGFA. In the HAWK and HARRIER clinical trials, brolucizumab (3 or 6mg) given 3 times monthly followed by every 12 weeks (with reduction to every 8 weeks if disease activity was noted) was compared to aflibercept 2mg given every 8 weeks. At week 48, brolucizumab was non-inferior to aflibercept for change in vision. Anatomic outcomes were more favorable in the brolucizumab groups, as compared to aflibercept. There were no differences in adverse events in the trial.[68]  Post-market reports reported cases of intraocular inflammation (IOI), including cases with occlusive retinal vasculitis with severe vision loss after brolucizumab injection.[69, 70, 71, 72]

An independent Safety Review Committee analyzed investigator re-viewed reports of intraocular inflammation, endophthalmitis, and retinal artery occlusion from the HAWK and HARRIER studies and identified 50 eyes with IOI, retinal vasculitis, and/or vascular occlusion. According to the committee, the incidence of IOI was 4.6%, including 3.3% with IOI with vasculitis and 2.1% with IOI with vasculitis and occlusion. The incidence of moderate vision loss (3 or more lines) was 0.74% and most of these cases involved IOI with vasculitis and occlusion.[73]  In light of these adverse events and the existence of other safe, effective anti-VEGF agents, brolicizumab is infrequently employed in the treatment of wet AMD.

Faricimab 6mg (Vabysmo, Genentech) is FDA approved for the treatment of wet AMD. Faricimab is a bispecfic antibody that dually inhibits both VEGFA and angiopoietin-2 (Ang2). Ang2 is a molecule in the angiogenisin1/Tie2 signaling axis that is implicated in angiogenesis and found to be elevated in eyes with wet AMD.[74, 75]  Studies in animal models demonstrate that Ang2 inhibition reduces vascular permeability and that dual inhibition of both Ang2 and VEGF results in greater reduction in vascular permeability than inhibition of either alone.[76]  Thus, dual inhibition of both of these pathways is thought to offer the potential of more potent clinical impact and in turn, longer durability. 

The TENAYA and LUCERNE clinical trials compared faricimab given every 16 weeks (with the option of reducing intervals to 8 or 12 weeks based on disease activity) to aflibercent 2mg given every 8 weeks. Visual acuity at 48 weeks was non-inferior in faricimab compared to aflibercept, with fewer injections. Approximately 78% of patients maintained treatment intervals of every 12 weeks or longer with faricimab. There were no differences in adverse events.[77]

Biosimilars are reverse-engineered from the reference anti-VEGF biologic to mimic the reference drug’s pharmokinetic endpoints and thus have similar efficacy and safety. The FDA approval pipeline for biosimilars is shorter than for new drugs, and costs of biosimilars are lower, offering the potential to significantly reduce the cost of treating wet AMD.[78, 79]  Biosimilars approved by the FDA for both wet AMD and myopic CNVM include: Byoovix (ranibizumab-nuna, Samsung Bioepis/Biogen)[78]  and Cimerli (ranibizumab-eqrn, Coherence Biosciences).[79]  Additional biosimilars are in the clinical trial and FDA approval pipeline.

Adverse effects after intravitreal injection include minor and common adverse events including conjunctival hyperemia or subconjunctival hemorrhage and post-injection, temporary ocular irritation/dryness.[80, 81, 82]  Vision threatening ocular adverse events include: iatrogenic cataract, retinal tear/detachment (0-0.67%),[81, 82]  and endophthalmitis (0.02-0.05%),[80, 81, 83, 84, 85]  and intraocular inflammation (variable).[57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 76, 77, 78, 79, 80, 81, 83, 84, 85]

Laser

Laser photocoagulation promotes regression of CNVM, but the laser itself creates a chorioretinal scar, resulting in a scotoma. Thus, laser is rarely employed for the treatment of most CNVMs, especially in light of effective pharmacologic therapy as outlined above. It is largely reserved in some cases of non-central or peripheral CNVMs.

Photodynamic therapy

Verteporfin-photodynamic therapy (PDT) involves intravenous injection of photosensitive dye (verteporfin) followed by application of laser, which activates the verteporfin to create free radicals that impact the endothelial cell membranes on choroidal neovascular membranes, resulting in their regression. The efficacy of verteporfin-PDT for CNVM in wet AMD was established in two large clinical trials, VIP and TAP.[86, 87]   However, the relative higher efficacy and better safety profile of pharmacologic agents has resulted in intravitreal injection therapy supplanting verteporfin-PDT for CNVM in wet AMD and most other conditions. Verteporfin-PDT may have a role, either alone or in combination with anti-VEGF therapy for CNVM due to PCV.[88, 89, 90]  

In the EVEREST II trial, patients treated with intravitreal ranibizumab plus verteporfin-PDT achieved superior vision gains, better polypoid lesion regression, and fewer overall treatments than those treated with ranibizumab alone.[89]  Other studies have found similar visual results, but better polyp regression with anti-VEGF versus antiVEGF combined with PDT.[90]  PDT is also useful in wet AMD cases with inadequate response to anti-VEGF injecitons or to reduce anti-VEGF treatment burden in wet AMD.[91, 92, 93]  

Surgical Care

Most CNVM do not require surgical care. Prior to the advent of effective pharmacologic and office-based therapies, surgery was performed in some cases to remove subfoveal CNVMs. However, results of studies such as the Submacular Surgery Trial demonstrated that submacular surgery is ineffective CNVM from AMD and POHS and often resulted in vision loss.[94, 95, 96, 97, 98]  Macular translocation surgery employed vitrectomy with 360-degree retinectomy to rotate the retina and in turn, change the position of the fovea away from the area of subfoveal CNVM. Visual outcomes were poor with macular translocation surgery, and there were significant complications such as bleeding, retinal detachment, proliferative vitreoretinopathy, macular holes, etc. There was also significant aniseikonia, high astigmatism, diplopia, enophthalmos, and cycloversion with retinal rotation procedures. Shortly after the advent of macular translocation surgery, anti-VEGF therapies became available for AMD. Thus, these surgeries are not employed currently for CNVM.[99, 100, 101, 102, 103, 104, 105, 106, 107]  

Surgery may be indicated for complications related to the CNVM such as vitreous hemorrhage or subretinal hemorrhage. Vitreous hemorrhage is a rare complication of massive hemorrhage from CNVM and, if not clearing spontaneously, may be removed via pars plana vitrectomy. Surgery may also be considered to displace large-subfoveal hemorrhage from CNVM, as such hemorrhage can be toxic to the outer retina. Such surgery involves vitrectomy, possible injection of subretinal tissue plasminogen activator (tPa), and placement of a partial gas bubble. The gas bubble, with appropriate head positioning, enables displacement of the hemorrhage inferiorly and out of the foveal region.[108, 109, 110, 111, 112]  Some clinicians attempt a similar approach without surgery involving in-office gas injection for pneumatic displacement, with or without intravitreal tPa injection.[113, 114, 115]  

Generally, patients undergoing surgery or in-office displacement also receive anti-VEGF therapy. These displacement approaches have been demonstrated effective at displacing fluid and in some cases, improving vision. However, there is also a risk of procedure-related complications such as retinal detachment, macular hole, and vitreous hemorrhage,[108, 109, 110, 111, 112, 113, 114, 115]  and vision improvement has also been noted with pharmacologic therapy with anti-VEGF alone.[116, 117]  There are no large trials comparing antiVEGF therapy alone versus in combination with displacement approaches. Displacement may be considered for larger hemorrhages that can be taken to the operating room promptly, ie, before the hemorrhage begins to organize.

Consultations

Patients with CNVM should be referred to a retinal specialist for appropriate diagnosis, treatment, and monitoring of the condition.

Diet

Higher dietary intake of lutein/zeaxanthin (found in nuts, oily fish, etc), carotenoids (found in dark green, leafy vegetables such as kale, spinach, arugula, mustard greens, collard greens, etc), as well as lower dietary intake of fats and high-glycemic index foods have been shown to be associated with reduced risk of advanced AMD (including CNVM).[118, 119, 120, 121]  In the Age-Related Eye Disease Study (AREDS and AREDS2), zinc combined with other antioxidants has been shown to reduce the progression rate of AMD to advanced stages such as wet AMD with CNVM, by approximately 25% in patients with intermediate stage AMD. No benefit has been demonstrated in eyes without AMD or early AMD.[47, 48, 49, 50, 51]

Activity

Smoking significantly increases the risk of CNVM development in patients with wet AMD and thus, smoking cessation should be encouraged.[122, 123, 124, 125]

Pegaptanib (Macugen)

Clinical Context:  A selective VEGF antagonist that promotes vision stability and reduces visual acuity loss and progression to legal blindness. VEGF causes angiogenesis and increases vascular permeability and inflammation, all of which contribute to neovascularization in age-related wet macular degeneration. Macugen is much less effective than bevacizumab, aflibercept, or ranibizumab.

Class Summary

Reduces risk of visual loss similar to that seen with photodynamic therapy.

Further Outpatient Care

As outlined above, treatment for CNVM often is ongoing. Even in those patients who achieve quiescence of CNVM and stop therapy, regular evaluations are required to assess for recurrent activity of the CNVM. In addition, patients are advised to monitor their vision, including with aides such as Amsler grid or home monitoring systems, and to report any changes in vision immediately.

Further Inpatient Care

All medical and surgical treatments for choroidal neovascular membranes (CNVMs) can be performed in an outpatient setting.

Transfer

Patients with CNVM should be referred to a retinal specialist for appropriate diagnosis, treatment, and monitoring of the condition.

Complications

CNVM or the exudation resulting from CNVM may result in damage to the RPE or outer retinal tissues, resulting in vision loss. RPE rips with associated vision loss may also occur in the setting of large PEDs with underlying CNVM, and this risk may be potentiated by rapid regression of the fibrovascular PED after treatment. Treatment is highly effective at mitigating damage and thus vision loss from CNVM. See above regarding potential complications of various CNVM treatments themselves.

Prognosis

The prognosis of CNVM is generally excellent when diagnosed and treated promptly. However, visual outcomes from long-term real world data suggests vision loss over time even in the era of anti-VEGF therapy, whereas clinical trials typically demonstrated visual acuity gains in the shorter term (1-2 years). Potential causes for long term vision loss include undertreatment and/or development of macular atrophy. Prognosis is worse in cases that present with significant subretinal hemorrhage or those diagnosed late due to presence of RPE and outer retinal damage.[57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 76, 77, 78, 79, 80, 81, 83, 84, 85]  

Patient Education

Patients should be educated about their diagnosis of CNVM, the cause, natural history, and treatment course. They should be instructed to monitor their vision, including with aides such as Amsler grid or home monitoring systems, and to report any changes in vision immediately.

Author

Mrinali Gupta, MD, Physician, Retina Associates of Orange County; Adjunct Clinical Assistant Professor of Ophthalmology, Keck School of Medicine of the University of Southern California

Disclosure: Nothing to disclose.

Specialty Editors

Simon K Law, MD, PharmD, Clinical Professor of Health Sciences, Department of Ophthalmology, Jules Stein Eye Institute, University of California, Los Angeles, David Geffen School of Medicine

Disclosure: Nothing to disclose.

Steve Charles, MD, Founder and CEO of Charles Retina Institute; Clinical Professor, Department of Ophthalmology, University of Tennessee College of Medicine

Disclosure: Received royalty and consulting fees for: Alcon Laboratories.

Chief Editor

Andrew A Dahl, MD, FACS, Assistant Professor of Surgery (Ophthalmology), New York College of Medicine (NYCOM); Director of Residency Ophthalmology Training, The Institute for Family Health and Mid-Hudson Family Practice Residency Program; Staff Ophthalmologist, Telluride Medical Center

Disclosure: Nothing to disclose.

Additional Contributors

Steve Charles, MD, Founder and CEO of Charles Retina Institute; Clinical Professor, Department of Ophthalmology, University of Tennessee College of Medicine

Disclosure: Received royalty and consulting fees for: Alcon Laboratories.

V Al Pakalnis, MD, PhD, Professor of Ophthalmology, University of South Carolina School of Medicine; Chief of Ophthalmology, Dorn Veterans Affairs Medical Center

Disclosure: Nothing to disclose.

References

  1. Grossniklaus HE, Green WR. Choroidal neovascularization. Am J Ophthalmol. 2004 Mar. 137 (3):496-503. [View Abstract]
  2. Yannuzzi LA, Sorenson J, Spaide RF, Lipson B. Idiopathic polypoidal choroidal vasculopathy (IPCV). Retina. 1990. 10 (1):1-8. [View Abstract]
  3. Rabb MF, Garoon I, LaFranco FP. Myopic macular degeneration. Int Ophthalmol Clin. 1981 Fall. 21 (3):51-69. [View Abstract]
  4. Gomolin JE. Choroidal neovascularization and central serous chorioretinopathy. Can J Ophthalmol. 1989 Feb. 24 (1):20-3. [View Abstract]
  5. Charbel Issa P, Gillies MC, Chew EY, Bird AC, Heeren TF, Peto T, et al. Macular telangiectasia type 2. Prog Retin Eye Res. 2013 May. 34:49-77. [View Abstract]
  6. Callanan D, Gass JD. Multifocal choroiditis and choroidal neovascularization associated with the multiple evanescent white dot and acute idiopathic blind spot enlargement syndrome. Ophthalmology. 1992 Nov. 99 (11):1678-85. [View Abstract]
  7. Agarwal A, Invernizzi A, Singh RB, Foulsham W, Aggarwal K, Handa S, et al. An update on inflammatory choroidal neovascularization: epidemiology, multimodal imaging, and management. J Ophthalmic Inflamm Infect. 2018 Sep 12. 8 (1):13. [View Abstract]
  8. Patel MM, Chee YE, Eliott D. Choroidal rupture: a review. Int Ophthalmol Clin. 2013 Fall. 53 (4):69-78. [View Abstract]
  9. Constantinides G, Corbel M, Turut T. [Angioid streaks and choroid neovascular membrane]. Bull Soc Ophtalmol Fr. 1974 Apr. 74 (4):493-7. [View Abstract]
  10. Bonnet M, Dubost Perret P, Grange JD. [29 cases of idiopathic choroidal neovessels in the young subject (pseudhistoplasmosis syndrome) followed from 6 months to 11 years]. Bull Soc Ophtalmol Fr. 1981 Nov. 81 (11):1059-61. [View Abstract]
  11. Gupta MP, Herzlich AA, Sauer T, Chan CC. Retinal Anatomy and Pathology. Dev Ophthalmol. 2016. 55: 7-17.
  12. Masland RH. The neuronal organization of the retina. Neuron. 2012 Oct 18. 76 (2):266-80. [View Abstract]
  13. Chirco KR, Sohn EH, Stone EM, Tucker BA, Mullins RF. Structural and molecular changes in the aging choroid: implications for age-related macular degeneration. Eye (Lond). 2017 Jan. 31 (1):10-25. [View Abstract]
  14. Subhi Y, Forshaw T, Sørensen TL. Macular thickness and volume in the elderly: A systematic review. Ageing Res Rev. 2016 Aug. 29:42-9. [View Abstract]
  15. Masland RH. Cell populations of the retina: the Proctor lecture. Invest Ophthalmol Vis Sci. 2011 Jun 28. 52 (7):4581-91. [View Abstract]
  16. Masland RH. The fundamental plan of the retina. Nat Neurosci. 2001 Sep. 4 (9):877-86. [View Abstract]
  17. Chee RI, Mahrous A, Koenig L, Mandel LS, Yazdanie F, Chan CC, et al. Histopathology of Age-Related Macular Degeneration and Implications for Pathogenesis and Therapy. Adv Exp Med Biol. 2021. 1256:67-88. [View Abstract]
  18. Booij JC, Baas DC, Beisekeeva J, Gorgels TG, Bergen AA. The dynamic nature of Bruch's membrane. Prog Retin Eye Res. 2010 Jan. 29 (1):1-18. [View Abstract]
  19. Freund KB, Ho IV, Barbazetto IA, Koizumi H, Laud K, Ferrara D, et al. Type 3 neovascularization: the expanded spectrum of retinal angiomatous proliferation. Retina. 2008 Feb. 28 (2):201-11. [View Abstract]
  20. Yannuzzi LA, Negrão S, Iida T, Carvalho C, Rodriguez-Coleman H, Slakter J, et al. Retinal angiomatous proliferation in age-related macular degeneration. Retina. 2001. 21 (5):416-34. [View Abstract]
  21. Grossniklaus HE, Green WR. Histopathologic and ultrastructural findings of surgically excised choroidal neovascularization. Submacular Surgery Trials Research Group. Arch Ophthalmol. 1998 Jun. 116 (6):745-9. [View Abstract]
  22. Grossniklaus HE, Miskala PH, Green WR, Bressler SB, Hawkins BS, Toth C, et al. Histopathologic and ultrastructural features of surgically excised subfoveal choroidal neovascular lesions: submacular surgery trials report no. 7. Arch Ophthalmol. 2005 Jul. 123 (7):914-21. [View Abstract]
  23. Rein DB, Wittenborn JS, Burke-Conte Z, Gulia R, Robalik T, Ehrlich JR, et al. Prevalence of Age-Related Macular Degeneration in the US in 2019. JAMA Ophthalmol. 2022 Dec 1. 140 (12):1202-1208. [View Abstract]
  24. Wong WL, Su X, Li X, Cheung CM, Klein R, Cheng CY, et al. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet Glob Health. 2014 Feb. 2 (2):e106-16. [View Abstract]
  25. Keane PA, Liakopoulos S, Chang KT, Wang M, Dustin L, Walsh AC, et al. Relationship between optical coherence tomography retinal parameters and visual acuity in neovascular age-related macular degeneration. Ophthalmology. 2008 Dec. 115 (12):2206-14. [View Abstract]
  26. Cukras C, Wang YD, Meyerle CB, Forooghian F, Chew EY, Wong WT. Optical coherence tomography-based decision making in exudative age-related macular degeneration: comparison of time- vs spectral-domain devices. Eye (Lond). 2010 May. 24 (5):775-83. [View Abstract]
  27. Fung AE, Lalwani GA, Rosenfeld PJ, Dubovy SR, Michels S, Feuer WJ, et al. An optical coherence tomography-guided, variable dosing regimen with intravitreal ranibizumab (Lucentis) for neovascular age-related macular degeneration. Am J Ophthalmol. 2007 Apr. 143 (4):566-83. [View Abstract]
  28. Regatieri CV, Branchini L, Duker JS. The role of spectral-domain OCT in the diagnosis and management of neovascular age-related macular degeneration. Ophthalmic Surg Lasers Imaging. 2011 Jul. 42 Suppl:S56-66. [View Abstract]
  29. Rogers AH, Martidis A, Greenberg PB, Puliafito CA. Optical coherence tomography findings following photodynamic therapy of choroidal neovascularization. Am J Ophthalmol. 2002 Oct. 134 (4):566-76. [View Abstract]
  30. Eter N, Spaide RF. Comparison of fluorescein angiography and optical coherence tomography for patients with choroidal neovascularization after photodynamic therapy. Retina. 2005 Sep. 25 (6):691-6. [View Abstract]
  31. Huang D, Swanson EA, Lin CP, Schuman JS, Stinson WG, Chang W, et al. Optical coherence tomography. Science. 1991 Nov 22. 254 (5035):1178-81. [View Abstract]
  32. Hee MR, Baumal CR, Puliafito CA, Duker JS, Reichel E, Wilkins JR, et al. Optical coherence tomography of age-related macular degeneration and choroidal neovascularization. Ophthalmology. 1996 Aug. 103 (8):1260-70. [View Abstract]
  33. Coscas F, Coscas G, Souied E, Tick S, Soubrane G. Optical coherence tomography identification of occult choroidal neovascularization in age-related macular degeneration. Am J Ophthalmol. 2007 Oct. 144 (4):592-9. [View Abstract]
  34. Guyer DR, Yannuzzi LA. Occult choroidal neovascularization. Yannuzzi LA, Flower RW, Slakter JS. Indocyanine green angiography. St. Louis, MO: Mosby; 199: 157-180.
  35. Coscas G, Coscas F, Zourdani A. Age-Related Macular Degeneration. Coscas G. Atlas of indocyanine green angiography fluorescein angiography, ICG angiography and OCT correlations. Elsevier; September 2005. 118.
  36. Yannuzzi LA, Slakter JS, Sorenson JA, Guyer DR, Orlock DA. Digital indocyanine green videoangiography and choroidal neovascularization. Retina. 1992. 12 (3):191-223. [View Abstract]
  37. Yannuzzi LA, Negrão S, Iida T, Carvalho C, Rodriguez-Coleman H, Slakter J, et al. Retinal angiomatous proliferation in age-related macular degeneration. Retina. 2001. 21 (5):416-34. [View Abstract]
  38. Freund KB, Ho IV, Barbazetto IA, Koizumi H, Laud K, Ferrara D, et al. Type 3 neovascularization: the expanded spectrum of retinal angiomatous proliferation. Retina. 2008 Feb. 28 (2):201-11. [View Abstract]
  39. Carnevali A, Cicinelli MV, Capuano V, Corvi F, Mazzaferro A, Querques L, et al. Optical Coherence Tomography Angiography: A Useful Tool for Diagnosis of Treatment-Naïve Quiescent Choroidal Neovascularization. Am J Ophthalmol. 2016 Sep. 169:189-198. [View Abstract]
  40. Jia Y, Bailey ST, Wilson DJ, Tan O, Klein ML, Flaxel CJ, et al. Quantitative optical coherence tomography angiography of choroidal neovascularization in age-related macular degeneration. Ophthalmology. 2014 Jul. 121 (7):1435-44. [View Abstract]
  41. Kuehlewein L, Bansal M, Lenis TL, Iafe NA, Sadda SR, Bonini Filho MA, et al. Optical Coherence Tomography Angiography of Type 1 Neovascularization in Age-Related Macular Degeneration. Am J Ophthalmol. 2015 Oct. 160 (4):739-48.e2. [View Abstract]
  42. Moorthy RS, Lyon AT, Rabb MF, Spaide RF, Yannuzzi LA, Jampol LM. Idiopathic polypoidal choroidal vasculopathy of the macula. Ophthalmology. 1998 Aug. 105 (8):1380-5. [View Abstract]
  43. Kokame GT, Omizo JN, Kokame KA, Yamane ML. Differentiating Exudative Macular Degeneration and Polypoidal Choroidal Vasculopathy Using OCT B-Scan. Ophthalmol Retina. 2021 Oct. 5 (10):954-961. [View Abstract]
  44. Cheung CMG, Lai TYY, Teo K, Ruamviboonsuk P, Chen SJ, Kim JE, et al. Polypoidal Choroidal Vasculopathy: Consensus Nomenclature and Non-Indocyanine Green Angiograph Diagnostic Criteria from the Asia-Pacific Ocular Imaging Society PCV Workgroup. Ophthalmology. 2021 Mar. 128 (3):443-452. [View Abstract]
  45. Spaide RF, Yannuzzi LA, Slakter JS, Sorenson J, Orlach DA. Indocyanine green videoangiography of idiopathic polypoidal choroidal vasculopathy. Retina. 1995. 15 (2):100-10. [View Abstract]
  46. de Carlo TE, Kokame GT, Kaneko KN, Lian R, Lai JC, Wee R. SENSITIVITY AND SPECIFICITY OF DETECTING POLYPOIDAL CHOROIDAL VASCULOPATHY WITH EN FACE OPTICAL COHERENCE TOMOGRAPHY AND OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY. Retina. 2019 Jul. 39 (7):1343-1352. [View Abstract]
  47. Age-Related Eye Disease Study Research Group. The Age-Related Eye Disease Study (AREDS): design implications. AREDS report no. 1. Control Clin Trials. 1999 Dec. 20 (6):573-600. [View Abstract]
  48. Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol. 2001 Oct. 119 (10):1417-36. [View Abstract]
  49. Chew EY, Clemons TE, Agrón E, Launer LJ, Grodstein F, Bernstein PS, et al. Effect of Omega-3 Fatty Acids, Lutein/Zeaxanthin, or Other Nutrient Supplementation on Cognitive Function: The AREDS2 Randomized Clinical Trial. JAMA. 2015 Aug 25. 314 (8):791-801. [View Abstract]
  50. Aronow ME, Chew EY. Age-related Eye Disease Study 2: perspectives, recommendations, and unanswered questions. Curr Opin Ophthalmol. 2014 May. 25 (3):186-90. [View Abstract]
  51. Age-Related Eye Disease Study 2 (AREDS2) Research Group, Chew EY, Clemons TE, et al. Secondary analyses of the effects of lutein/zeaxanthin on age-related macular degeneration progression: AREDS2 report No. 3. JAMA Ophthalmol. 2014 Feb. 132 (2):142-9. [View Abstract]
  52. Martin G, Schlunck G, Hansen LL, Agostini HT. Differential expression of angioregulatory factors in normal and CNV-derived human retinal pigment epithelium. Graefes Arch Clin Exp Ophthalmol. 2004 Apr. 242 (4):321-6. [View Abstract]
  53. Mousa SA, Lorelli W, Campochiaro PA. Role of hypoxia and extracellular matrix-integrin binding in the modulation of angiogenic growth factors secretion by retinal pigmented epithelial cells. J Cell Biochem. 1999 Jul 1. 74 (1):135-43. [View Abstract]
  54. Wells JA, Murthy R, Chibber R, Nunn A, Molinatti PA, Kohner EM, et al. Levels of vascular endothelial growth factor are elevated in the vitreous of patients with subretinal neovascularisation. Br J Ophthalmol. 1996 Apr. 80 (4):363-6. [View Abstract]
  55. VEGF Inhibition Study in Ocular Neovascularization (V.I.S.I.O.N.) Clinical Trial Group, Chakravarthy U, Adamis AP, Cunningham ET Jr, Goldbaum M, Guyer DR, et al. Year 2 efficacy results of 2 randomized controlled clinical trials of pegaptanib for neovascular age-related macular degeneration. Ophthalmology. 2006 Sep. 113 (9):1508.e1-25. [View Abstract]
  56. VEGF Inhibition Study in Ocular Neovascularization (V.I.S.I.O.N.) Clinical Trial Group, D'Amico DJ, Masonson HN, Patel M, Adamis AP, Cunningham ET Jr, et al. Pegaptanib sodium for neovascular age-related macular degeneration: two-year safety results of the two prospective, multicenter, controlled clinical trials. Ophthalmology. 2006 Jun. 113 (6):992-1001.e6. [View Abstract]
  57. Avery RL, Pieramici DJ, Rabena MD, et al. Intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration. Ophthalmology. 2006 Mar. 113 (3):363-372.e5. [View Abstract]
  58. Spaide RF, Laud K, Fine HF, Klancnik JM Jr, Meyerle CB, Yannuzzi LA, et al. Intravitreal bevacizumab treatment of choroidal neovascularization secondary to age-related macular degeneration. Retina. 2006 Apr. 26 (4):383-90. [View Abstract]
  59. Brown DM, Kaiser PK, Michels M, Soubrane G, Heier JS, Kim RY, et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med. 2006 Oct 5. 355 (14):1432-44. [View Abstract]
  60. 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. 2006 Oct 5. 355 (14):1419-31. [View Abstract]
  61. Ho AC, Busbee BG, Regillo CD, Wieland MR, Van Everen SA, Li Z, et al. Twenty-four-month efficacy and safety of 0.5 mg or 2.0 mg ranibizumab in patients with subfoveal neovascular age-related macular degeneration. Ophthalmology. 2014 Nov. 121 (11):2181-92. [View Abstract]
  62. Abraham P, Yue H, Wilson L. Randomized, double-masked, sham-controlled trial of ranibizumab for neovascular age-related macular degeneration: PIER study year 2. Am J Ophthalmol. 2010 Sep. 150 (3):315-324.e1. [View Abstract]
  63. Rofagha S, Bhisitkul RB, Boyer DS, Sadda SR, Zhang K, SEVEN-UP Study Group. Seven-year outcomes in ranibizumab-treated patients in ANCHOR, MARINA, and HORIZON: a multicenter cohort study (SEVEN-UP). Ophthalmology. 2013 Nov. 120 (11):2292-9. [View Abstract]
  64. Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group, Martin DF, Maguire MG, Fine SL, Ying GS, Jaffe GJ, et al. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results. Ophthalmology. 2012 Jul. 119 (7):1388-98. [View Abstract]
  65. Freund KB, Korobelnik JF, Devenyi R, Framme C, Galic J, Herbert E, et al. TREAT-AND-EXTEND REGIMENS WITH ANTI-VEGF AGENTS IN RETINAL DISEASES: A Literature Review and Consensus Recommendations. Retina. 2015 Aug. 35 (8):1489-506. [View Abstract]
  66. Heier JS, Brown DM, Chong V, et al. Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology. 2012 Dec. 119 (12):2537-48. [View Abstract]
  67. Brown DM; on behalf of the PULSAR study investigators. Aflibercept 8 mg in patients with nAMD: 48-week results from the phase 3 PULSAR trial. Data presented at: Angiogenesis 2023; February 11, 2023.
  68. Dugel PU, Koh A, Ogura Y, Jaffe GJ, Schmidt-Erfurth U, Brown DM, et al. HAWK and HARRIER: Phase 3, Multicenter, Randomized, Double-Masked Trials of Brolucizumab for Neovascular Age-Related Macular Degeneration. Ophthalmology. 2020 Jan. 127 (1):72-84. [View Abstract]
  69. Haug SJ, Hien DL, Uludag G, Ngoc TTT, Lajevardi S, Halim MS, et al. Retinal arterial occlusive vasculitis following intravitreal brolucizumab administration. Am J Ophthalmol Case Rep. 2020 Jun. 18:100680. [View Abstract]
  70. Baumal CR, Spaide RF, Vajzovic L, Freund KB, Walter SD, John V, et al. Retinal Vasculitis and Intraocular Inflammation after Intravitreal Injection of Brolucizumab. Ophthalmology. 2020 Oct. 127 (10):1345-1359. [View Abstract]
  71. Jain A, Chea S, Matsumiya W, Halim MS, Yaşar Ç, Kuang G, et al. Severe vision loss secondary to retinal arteriolar occlusions after multiple intravitreal brolucizumab administrations. Am J Ophthalmol Case Rep. 2020 Jun. 18:100687. [View Abstract]
  72. Witkin AJ, Hahn P, Murray TG, Arevalo JF, Blinder KJ, Choudhry N, et al. Occlusive Retinal Vasculitis Following Intravitreal Brolucizumab. J Vitreoretin Dis. 2020 Jul. 4 (4):269-279. [View Abstract]
  73. Monés J, Srivastava SK, Jaffe GJ, et al. Risk of Inflammation, Retinal Vasculitis, and Retinal Occlusion-Related Events with Brolucizumab: Post Hoc Review of HAWK and HARRIER. Ophthalmology. 2021 Jul. 128 (7):1050-1059. [View Abstract]
  74. Peters S, Cree IA, Alexander R, Turowski P, Ockrim Z, Patel J, et al. Angiopoietin modulation of vascular endothelial growth factor: Effects on retinal endothelial cell permeability. Cytokine. 2007 Nov. 40 (2):144-50. [View Abstract]
  75. Ng DS, Yip YW, Bakthavatsalam M, Chen LJ, Ng TK, Lai TY, et al. Elevated angiopoietin 2 in aqueous of patients with neovascular age related macular degeneration correlates with disease severity at presentation. Sci Rep. 2017 Mar 27. 7:45081. [View Abstract]
  76. Regula JT, Lundh von Leithner P, Foxton R, Barathi VA, Cheung CM, Bo Tun SB, et al. Targeting key angiogenic pathways with a bispecific CrossMAb optimized for neovascular eye diseases. EMBO Mol Med. 2016 Nov. 8 (11):1265-1288. [View Abstract]
  77. Heier JS, Khanani AM, Quezada Ruiz C, Basu K, Ferrone PJ, Brittain C, et al. Efficacy, durability, and safety of intravitreal faricimab up to every 16 weeks for neovascular age-related macular degeneration (TENAYA and LUCERNE): two randomised, double-masked, phase 3, non-inferiority trials. Lancet. 2022 Feb 19. 399 (10326):729-740. [View Abstract]
  78. Bressler NM, Veith M, Hamouz J, Ernest J, Zalewski D, Studnička J, et al. Biosimilar SB11 versus reference ranibizumab in neovascular age-related macular degeneration: 1-year phase III randomised clinical trial outcomes. Br J Ophthalmol. 2023 Mar. 107 (3):384-391. [View Abstract]
  79. Holz FG, Oleksy P, Ricci F, Kaiser PK, Kiefer J, Schmitz-Valckenberg S, et al. Efficacy and Safety of Biosimilar FYB201 Compared with Ranibizumab in Neovascular Age-Related Macular Degeneration. Ophthalmology. 2022 Jan. 129 (1):54-63. [View Abstract]
  80. Falavarjani KG, Nguyen QD. Adverse events and complications associated with intravitreal injection of anti-VEGF agents: a review of literature. Eye (Lond). 2013 Jul. 27 (7):787-94. [View Abstract]
  81. Tolentino M. Systemic and ocular safety of intravitreal anti-VEGF therapies for ocular neovascular disease. Surv Ophthalmol. 2011 Mar-Apr. 56 (2):95-113. [View Abstract]
  82. Meyer CH, Michels S, Rodrigues EB, Hager A, Mennel S, Schmidt JC, et al. Incidence of rhegmatogenous retinal detachments after intravitreal antivascular endothelial factor injections. Acta Ophthalmol. 2011 Feb. 89 (1):70-5. [View Abstract]
  83. Fintak DR, Shah GK, Blinder KJ, Regillo CD, Pollack J, Heier JS, et al. Incidence of endophthalmitis related to intravitreal injection of bevacizumab and ranibizumab. Retina. 2008 Nov-Dec. 28 (10):1395-9. [View Abstract]
  84. Moshfeghi AA, Rosenfeld PJ, Flynn HW Jr, Schwartz SG, Davis JL, Murray TG, et al. Endophthalmitis after intravitreal vascular [corrected] endothelial growth factor antagonists: a six-year experience at a university referral center. Retina. 2011 Apr. 31 (4):662-8. [View Abstract]
  85. McCannel CA. Meta-analysis of endophthalmitis after intravitreal injection of anti-vascular endothelial growth factor agents: causative organisms and possible prevention strategies. Retina. 2011 Apr. 31 (4):654-61. [View Abstract]
  86. Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: one-year results of 2 randomized clinical trials--TAP report. Treatment of age-related macular degeneration with photodynamic therapy (TAP) Study Group. Arch Ophthalmol. 1999 Oct. 117 (10):1329-45. [View Abstract]
  87. Verteporfin in Photodynamic Therapy Study Group. 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 May. 108 (5):841-52. [View Abstract]
  88. Wataru K, Sugiyama A, Yoneyama S, Matsubara M, Fukuda Y, Parikh R, et al. Five-year outcomes of photodynamic therapy combined with intravitreal injection of ranibizumab or aflibercept for polypoidal choroidal vasculopathy. PLoS One. 2020. 15 (2):e0229231. [View Abstract]
  89. Lim TH, Lai TYY, Takahashi K, Wong TY, Chen LJ, Ruamviboonsuk P, et al. Comparison of Ranibizumab With or Without Verteporfin Photodynamic Therapy for Polypoidal Choroidal Vasculopathy: The EVEREST II Randomized Clinical Trial. JAMA Ophthalmol. 2020 Sep 1. 138 (9):935-942. [View Abstract]
  90. Miyakubo T, Mukai R, Matsumoto H, Morimoto M, Takahashi M, Nagai K, et al. Comparison of the 2-Year Results of Photodynamic Therapy with Aflibercept and Aflibercept Monotherapy for Polypoidal Choroidal Vasculopathy. Clin Ophthalmol. 2023. 17:571-577. [View Abstract]
  91. Gao Y, Yu T, Zhang Y, Dang G. Anti-VEGF Monotherapy Versus Photodynamic Therapy and Anti-VEGF Combination Treatment for Neovascular Age-Related Macular Degeneration: A Meta-Analysis. Invest Ophthalmol Vis Sci. 2018 Aug 1. 59 (10):4307-4317. [View Abstract]
  92. Wada I, Shiose S, Ishikawa K, Kano K, Notomi S, Mori K, et al. One-year efficacy of "rescue photodynamic therapy" for patients with typical age-related macular degeneration, polypoidal choroidal vasculopathy, and pachychoroid neovasculopathy refractory to anti-vascular endothelial growth factor therapy. Graefes Arch Clin Exp Ophthalmol. 2022 Jun. 260 (6):2029-2036. [View Abstract]
  93. Park UC, Kim BH, Choe HR, Yeon DY, Yu HG. Long-term results of rescue photodynamic therapy for type 1 neovascularization refractory to anti-vascular endothelial growth factor. Acta Ophthalmol. 2021 Sep. 99 (6):e899-e907. [View Abstract]
  94. Thomas MA, Kaplan HJ. Surgical removal of subfoveal neovascularization in the presumed ocular histoplasmosis syndrome. Am J Ophthalmol. 1991 Jan 15. 111 (1):1-7. [View Abstract]
  95. Schmidt JC, Rodrigues EB, Meyer CH, Kroll P. Is membrane extraction in cases of exudative age-related macular degeneration still up-to-date? A 4-year résumé. Ophthalmologica. 2003 Nov-Dec. 217 (6):401-7. [View Abstract]
  96. Pollack JS, Del Priore LV, Smith ME, Feiner MA, Kaplan HJ. Postoperative abnormalities of the choriocapillaris in exudative age-related macular degeneration. Br J Ophthalmol. 1996 Apr. 80 (4):314-8. [View Abstract]
  97. Castellarin AA, Nasir M, Sugino IK, Zarbin MA. Progressive presumed choriocapillaris atrophy after surgery for age-related macular degeneration. Retina. 1998. 18 (2):143-9. [View Abstract]
  98. Bressler NM, Bressler SB, Hawkins BS, Marsh MJ, Sternberg P Jr, Thomas MA, et al. Submacular surgery trials randomized pilot trial of laser photocoagulation versus surgery for recurrent choroidal neovascularization secondary to age-related macular degeneration: I. Ophthalmic outcomes submacular surgery trials pilot study report number 1. Am J Ophthalmol. 2000 Oct. 130 (4):387-407. [View Abstract]
  99. Glacet-Bernard A, Kuhn D, Coscas F, Coscas G, Soubrane G. [Translocation of the macula for retrofoveal choroidal neovascularization in age-related macular degeneration and severe myopia: first results]. J Fr Ophtalmol. 2000 Jun. 23 (6):576-81. [View Abstract]
  100. Lewis H. Macular translocation with chorioscleral outfolding: a pilot clinical study. Am J Ophthalmol. 2001 Aug. 132 (2):156-63. [View Abstract]
  101. Aisenbrey S, Lafaut BA, Szurman P, Grisanti S, Lüke C, Krott R, et al. Macular translocation with 360 degrees retinotomy for exudative age-related macular degeneration. Arch Ophthalmol. 2002 Apr. 120 (4):451-9. [View Abstract]
  102. Mruthyunjaya P, Stinnett SS, Toth CA. Change in visual function after macular translocation with 360 degrees retinectomy for neovascular age-related macular degeneration. Ophthalmology. 2004 Sep. 111 (9):1715-24. [View Abstract]
  103. Toth CA, Lapolice DJ, Banks AD, Stinnett SS. Improvement in near visual function after macular translocation surgery with 360-degree peripheral retinectomy. Graefes Arch Clin Exp Ophthalmol. 2004 Jul. 242 (7):541-8. [View Abstract]
  104. Pawlak D, Glacet-Bernard A, Papp M, Roquet W, Coscas G, Soubrane G. Limited macular translocation compared with photodynamic therapy in the management of subfoveal choroidal neovascularization in age-related macular degeneration. Am J Ophthalmol. 2004 May. 137 (5):880-7. [View Abstract]
  105. Khurana RN, Fujii GY, Walsh AC, Humayun MS, de Juan E Jr, Sadda SR. Rapid recurrence of geographic atrophy after full macular translocation for nonexudative age-related macular degeneration. Ophthalmology. 2005 Sep. 112 (9):1586-91. [View Abstract]
  106. Falkner CI, Leitich H, Frommlet F, Bauer P, Binder S. The end of submacular surgery for age-related macular degeneration? A meta-analysis. Graefes Arch Clin Exp Ophthalmol. 2007 Apr. 245 (4):490-501. [View Abstract]
  107. Gelisken F, Voelker M, Schwabe R, Besch D, Aisenbrey S, Szurman P, et al. Full macular translocation versus photodynamic therapy with verteporfin in the treatment of neovascular age-related macular degeneration: 1-year results of a prospective, controlled, randomised pilot trial (FMT-PDT). Graefes Arch Clin Exp Ophthalmol. 2007 Aug. 245 (8):1085-95. [View Abstract]
  108. Tognetto D, Skiadaresi E, Cecchini P, Ravalico G. Subretinal recombinant tissue plasminogen activator and pneumatic displacement for the management of subretinal hemorrhage occurring after anti-VEGF injections for wet AMD. Clin Ophthalmol. 2011. 5:459-63. [View Abstract]
  109. Chang W, Garg SJ, Maturi R, Hsu J, Sivalingam A, Gupta SA, et al. Management of thick submacular hemorrhage with subretinal tissue plasminogen activator and pneumatic displacement for age-related macular degeneration. Am J Ophthalmol. 2014 Jun. 157 (6):1250-7. [View Abstract]
  110. Boiché M, Angioi-Duprez K, Conart JB, Berrod JP. Treatment of hematomas in age related macular degeneration by vitrectomy and subretinal injection of r-tPA: Preliminary results. J Fr Ophtalmol. 2019 Nov. 42 (9):e391-e397. [View Abstract]
  111. Jackson TL, Bunce C, Desai R, Hillenkamp J, Lee CN, Lois N, et al. Vitrectomy, subretinal Tissue plasminogen activator and Intravitreal Gas for submacular haemorrhage secondary to Exudative Age-Related macular degeneration (TIGER): study protocol for a phase 3, pan-European, two-group, non-commercial, active-control, observer-masked, superiority, randomised controlled surgical trial. Trials. 2022 Jan 31. 23 (1):99. [View Abstract]
  112. Iannetta D, De Maria M, Bolletta E, Mastrofilippo V, Moramarco A, Fontana L. Subretinal Injection of Recombinant Tissue Plasminogen Activator and Gas Tamponade to Displace Acute Submacular Haemorrhages Secondary to Age-Related Macular Degeneration. Clin Ophthalmol. 2021. 15:3649-3659. [View Abstract]
  113. Ron Y, Ehrlich R, Axer-Siegel R, Rosenblatt I, Weinberger D. Pneumatic displacement of submacular hemorrhage due to age-related macular degeneration. Ophthalmologica. 2007. 221 (1):57-61. [View Abstract]
  114. Daneshvar H, Kertes PJ, Leonard BC, Peyman GA. Management of submacular hemorrhage with intravitreal sulfur hexafluoride: a pilot study. Can J Ophthalmol. 1999 Dec. 34 (7):385-8. [View Abstract]
  115. Kitagawa Y, Shimada H, Mori R, Tanaka K, Yuzawa M. Intravitreal Tissue Plasminogen Activator, Ranibizumab, and Gas Injection for Submacular Hemorrhage in Polypoidal Choroidal Vasculopathy. Ophthalmology. 2016 Jun. 123 (6):1278-86. [View Abstract]
  116. Shienbaum G, Garcia Filho CA, Flynn HW Jr, Nunes RP, Smiddy WE, Rosenfeld PJ. Management of submacular hemorrhage secondary to neovascular age-related macular degeneration with anti-vascular endothelial growth factor monotherapy. Am J Ophthalmol. 2013 Jun. 155 (6):1009-13. [View Abstract]
  117. Iyer PG, Brooks HL Jr, Flynn HW Jr. Long-Term Favorable Visual Outcomes in Patients with Large Submacular Hemorrhage. Clin Ophthalmol. 2021. 15:1189-1192. [View Abstract]
  118. Mares-Perlman JA, Brady WE, Klein R, VandenLangenberg GM, Klein BE, Palta M. Dietary fat and age-related maculopathy. Arch Ophthalmol. 1995 Jun. 113 (6):743-8. [View Abstract]
  119. Seddon JM, Ajani UA, Sperduto RD, Hiller R, Blair N, Burton TC, et al. Dietary carotenoids, vitamins A, C, and E, and advanced age-related macular degeneration. Eye Disease Case-Control Study Group. JAMA. 1994 Nov 9. 272 (18):1413-20. [View Abstract]
  120. Age-Related Eye Disease Study Research Group, SanGiovanni JP, Chew EY, Clemons TE, Ferris FL 3rd, Gensler G, et al. The relationship of dietary carotenoid and vitamin A, E, and C intake with age-related macular degeneration in a case-control study: AREDS Report No. 22. Arch Ophthalmol. 2007 Sep. 125 (9):1225-32. [View Abstract]
  121. Chiu CJ, Milton RC, Gensler G, Taylor A. Association between dietary glycemic index and age-related macular degeneration in nondiabetic participants in the Age-Related Eye Disease Study. Am J Clin Nutr. 2007 Jul. 86 (1):180-8. [View Abstract]
  122. Paetkau ME, Boyd TA, Grace M, Bach-Mills J, Winship B. Senile disciform macular degeneration and smoking. Can J Ophthalmol. 1978 Apr. 13 (2):67-71. [View Abstract]
  123. Vinding T, Appleyard M, Nyboe J, Jensen G. Risk factor analysis for atrophic and exudative age-related macular degeneration. An epidemiological study of 1000 aged individuals. Acta Ophthalmol (Copenh). 1992 Feb. 70 (1):66-72. [View Abstract]
  124. Risk factors for neovascular age-related macular degeneration. The Eye Disease Case-Control Study Group. Arch Ophthalmol. 1992 Dec. 110 (12):1701-8. [View Abstract]
  125. Klein R, Klein BE, Linton KL, DeMets DL. The Beaver Dam Eye Study: the relation of age-related maculopathy to smoking. Am J Epidemiol. 1993 Jan 15. 137 (2):190-200. [View Abstract]