Choroidal Neovascular Membranes 

Updated: Mar 01, 2017
Author: Steve Charles, MD; Chief Editor: Andrew A Dahl, MD, FACS 

Overview

Background

Choroidal neovascular membranes (CNVMs) are associated with many diseases. The most common causes are age-related macular degeneration (AMD),[1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26] presumed ocular histoplasmosis syndrome (POHS),[27] myopic macular degeneration,[28] trauma, and angioid streaks; however, many cases are idiopathic.

The natural history of patients with AMD should not be overlooked when pilot studies of new therapies are reported. In a randomized trial (of 481 patients) of interferon alpha-2, 62% of the placebo group stabilized at 1 year, losing less than 3 lines of vision. Randomized clinical trials are necessary in assessing treatment efficacy in cases of CNVM secondary to AMD as well as other causes. Submacular surgery, photodynamic therapy, translocation, and transpupillary thermotherapy (TTT) were once advocated as a means of stabilizing vision, where stable is defined a modest reduction in the rate of vision loss. True stabilization should be defined as no visual loss. A therapy that purports to stabilize vision requires large numbers of patients in a randomized trial with long-term follow-up to prove stabilization.

Clinical trials of ranibizumab not only showed true stabilization in approximately 75% of cases (ie, avoidance of 3 lines [15 ETDRS letters] of visual loss [defined as moderate visual loss]) but also 30-40% of patients had visual improvement.

Subfoveal CNVMs do not result in a loss of ambulatory vision if untreated. The natural history of subfoveal CNVMs never results in total blindness, while this outcome is all too frequent with macular translocation and occasionally with submacular surgery.[29]

Pathophysiology

CNVMs may be thought of as the initial phase of a choroidal scar. Because these structures angiographically demonstrate a network of vessels, they are often referred to as "nets." The early phase of these lesions is termed exudative, while the later phase is termed cicatricial. Increased permeability of new vessels to fluorescein and indocyanine green (ICG) creates the familiar angiographic appearance referred to as "leakage."

Vascular endothelial growth factor (VEGF) is present during the neovascularization phase. Because the scars are often circular in nature, they are called disciform scars when they enter the cicatricial phase. CNVMs, like all scarring disorders, seem to be a repair process with tissue loss or damage initiating the repair activity. The cause of tissue destruction in AMD is probably apoptosis, programmed cellular death. POHS, trauma, laser therapy, and angioid streaks all have in common a defect in the retinal pigment epithelium (RPE) and/or choriocapillaris.[30, 11, 31, 32, 33] Genetic abnormalities, specifically single polynucleotide polymorphism in the alternative complement pathway and reactive oxygen species, play a specific role in AMD.

Epidemiology

Frequency

United States

The overall prevalence of neovascular AMD in people older than 40 years is estimated to be 1.47%. The prevalence increases with advancing age. Patients in their 70s are more likely to have AMD than patients in their 60s, and patients in their 80s are more likely to have wet AMD than patients in their 70s.[34, 35]

International

Polypoidal choroidal vasculopathy, which is a risk factor for CNVMs, is more common in Asian patients than in white patients.[36]

Myopia, which is also a risk factor for CNVMs, is more common in Asian patients than in white patients or black patients.

Mortality/Morbidity

CNVM and most related diseases are not characterized by increased mortality rates. Smoking increases the progression rate of AMD by 350-500%, and, of course, smoking dramatically increases cancer and cardiovascular death rates. Morbidity is limited to the loss of central vision; the peripheral vision is virtually always retained in cases of CNVM unless complications of surgical therapy occur.

Race

The incidence rate of AMD is less in blacks than in whites (see Age).

Other causes of CNVMs are not associated with differences in racial incidence, except for angioid streaks associated with sickle cell disease and ethnic differences in the incidence of myopia.

Sex

Ocular trauma is more common in men than in women and is a known cause of CNVMs. AMD is slightly more common in women than in men. No known significant sexual predilection exists for other causes of CNVMs.

Age

The prevalence of AMD increases rapidly with age.[22]

AMD is more common after age 60 years, with the frequency increasing for patients in their 70s and an even greater frequency for patients in their 80s. The frequency of AMD is 11.90% in white men older than 80 years and 16.39% in white women older than 80 years.

Histoplasmosis typically occurs in the 30s or 40s.

Angioid streaks occur in individuals aged 30-60 years.

Myopic macular degeneration typically occurs after age 25 years.

Prognosis

Early diagnosis and immediate intervention with anti-VEGF therapy are crucial to improving outcomes. The prognosis of all CNVMs is very good, regardless of cause, if anti-VEGF therapy is initiated before bleeding or scarring occurs. Many patients with AMD require treatment for many years. In general, patients who receive more injections have better outcomes. No known adverse events are associated with anti-VEGF therapy.

Patients treated with a monthly (31-42 days, no longer) regimen or treat-and-extend approach (preferred practice pattern) have a better prognosis than patients treated using a PRN strategy (ie, treatment administered only when subretinal fluid or intraretinal fluid is noted on optical coherence tomography [OCT] imaging).

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; it should not be limited to a scripted definition of "distortion." Office staff should be instructed that these patients should be seen within a few days and undergo OCT imaging and clinical examination.

 

Presentation

History

Patients with choroidal neovascular membranes (CNVMs) may report the following:[37, 38]

  • Decreased central vision
  • Central or paracentral, relative or absolute scotomas
  • Distortion (metamorphopsia)
  • Central light flashes or flickering
  • Impaired color vision
  • Prolonged recovery from light stress

Physical

Perform an examination using a slit lamp biomicroscopy and a fundus contact lens or 60-, 78-, or 90-diopter (D) lens. Fluorescein angiography (FA) is required in some cases. ICG angiography is useful in approximately 5-10% of cases. Optical coherence tomography (OCT) has become an essential part in the assessment of these patients.

Clinical findings

Grey or ill-defined CNVMs can be subfoveal, juxtafoveal, extrafoveal, peripapillary, or even in the periphery. Experienced observers often visualize these lesions without OCT imaging or angiography, although imaging is necessary in virtually all instances.[39, 40] OCT imaging has largely replaced angiography.

Subretinal hemorrhage is common and frequently outlines the CNVM. In some cases, very large choroidal and/or subretinal hemorrhages occur that can be mistaken for malignant melanomas of the choroid.

Exudate, serous fluid, or both are often present with choroidal neovascularization (CNV). Angiographically well-defined membranes are referred to as classic; these lesions are usually subretinal. In many cases, the neovascular membrane is ill-defined and is termed occult; these lesions are usually under the retinal pigment epithelium (RPE) and often associated with a pigment epithelial detachment (PED). Retinal angiomatous proliferation (RAP) can be seen clinically; the neovascularization is now thought to arise from the choroid. Polypoidal choroidal vasculopathy is virtually impossible to identify clinically but can be accompanied by exudate, subretinal fluid, and hemorrhage. Large amounts of subretinal blood, fluid, or exudate may prevent clinical or angiographic visualization of the underlying CNV.

Causes

AMD, POHS, myopia, trauma, angioid streaks, certain hereditary macular degenerations, and other causes of macular RPE damage have been associated with CNVM formation. Many cases are idiopathic.

 

Workup

Laboratory Studies

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

Hereditary macular degeneration can usually be identified from clinical presentation, family history, angiography, electroretinogram (ERG),[41] electro-oculogram (EOG),[42] 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 are usually due to pseudoxanthoma elasticum (PXE), but they have also been reported in patients with sickle cell disease and Paget disease.

Imaging Studies

FA and ICG angiography were historically used in confirming the diagnosis, in determining the efficacy of treatment, in determining the need for retreatment, and, rarely, in guiding laser and photodynamic therapy (PDT).[43, 44, 45, 46, 47, 48, 49] However, OCT imaging has largely replaced angiography.

Digital angiography offers the advantages of immediate viewing, local area network (LAN) and/or wide area network (WAN) access, archiving, and incorporation into the computerized medical record, but it offers no better resolution than film-based imaging. Confocal laser scanning-based imaging dramatically improves the signal to background ratio by 15 dB, provides better illumination of the fluorophore, and improves image quality as compared to a fundus camera-based digital imaging system.

ICG angiography is rarely needed. Retinal angiomatous proliferation (RAP) is relatively common and is best visualized with confocal angiography; however, careful contact lens examination is often sufficient.

Ocular coherence tomography has become an essential tool both in performing the initial workup and in determining the need for treatment and retreatment of patients with CNVMs.[50] The initial technology was based on time domain OCT (Zeiss Stratus III), which served the vitreoretinal community well; however, the recent transition to spectral domain OCT provides far better axial and lateral resolution.[51] It is routinely possible to identify the CNVM, not just the presence of subretinal fluid, PED, and overlying retinal edema. Swept source OCT imaging may prove to be somewhat better than spectral domain OCT imaging. OCT angiography has not been shown to be of value, although there is substantial marketing pressure.

Histologic Findings

Biopsy is not performed in CNVM cases. If submacular surgery is performed for non-AMD cases in very rare instances, histology is not needed, as many of these lesions have been studied; histology is of no value to the patient.[52, 53]

 

Treatment

Medical Care

Zinc/antioxidant therapy

In the Age-Related Eye Disease Study (AREDS), zinc combined with other antioxidants has been shown to reduce the progression rate of AMD by approximately 25% in patients with intermediate drusen.[54]

Intravitreal injection

Ranibizumab (Lucentis) is an anti-VEGF monoclonal antibody fragment. Intravitreal ranibizumab is safe and effective in stabilizing and improving vision in patients with choroidal neovascularization (CNV) caused by pathological myopia with a low number of injections.[55] The US Food and Drug Administration (FDA)-approved dose of ranibizumab is 0.5 mg (0.05 mL) administered by intravitreal injection[56, 57] for exudative AMD.

In pivotal Phase III clinical trials involving treatment of neovascular age-related macular degeneration (AMD), ranibizumab was administered once a month for up to 2 years.[58, 59, 60] The benefits of treatment with ranibizumab were also maintained in most patients for up to 2 years with continuous use. Treatment should be continued and monitored. Individual results may vary. In the pivotal clinical trials, some patients reported an improvement in vision starting at day 7 after treatment with ranibizumab. However, just because a patient does not report an immediate improvement, it does not mean that ranibizumab is not working. Some patients experience improvements later or merely do not lose significant vision with ranibizumab.

Compared to continual monthly dosing, dosing every 3 months will lead to an approximate 5-letter (1-line) loss of visual acuity benefit, on average, over the following 9 months. Patients should be evaluated regularly according to the package label.

Monthly injections were used in the pivotal clinical trials, but many retinal specialists have switched to a treat-and-extend paradigm primarily using OCT evidence of subretinal fluid and/or retinal edema as an indication for retreatment. Because of the concern that recurrences occasionally result in poor outcomes, most retinal specialists now use a treat-and-extend strategy; injections are given after leakage is eliminated, and the follow-up interval is extended to 6 weeks. If the lesion is dry at 6 weeks, another injection is given, and the follow-up interval is extended to 8 weeks.

Ranibizumab sets a new standard in the treatment of neovascular AMD because it is the first therapy proven to improve vision instead of simply slowing the decline of central vision loss. In clinical trials, up to 40% of patients gained 15 or more letters of vision and nearly all patients (up to 96%) maintained vision.

Of patients treated with ranibizumab, 94% remained on therapy for 1 year versus 89% of patients in the control groups. Ranibizumab has been studied in more than 1000 patients with neovascular AMD in 2 double-masked, controlled 2-year studies.

Ranibizumab is indicated for the treatment of patients with neovascular (wet) AMD.

Ranibizumab is contraindicated in patients with ocular or periocular infections.

Intravitreal injections, including those with ranibizumab, have been associated with endophthalmitis and retinal detachment.[61] Proper aseptic injection technique should always be used when administering ranibizumab. Patients should be monitored during the week following the injection to permit early treatment, should an infection occur.

Increases in intraocular pressure (IOP) have been noted within 60 minutes of intravitreal injection. IOP and perfusion of the optic nerve head should be monitored and managed appropriately.

Although a low rate (< 4%) of arterial thromboembolic events (ATEs) was observed in one ranibizumab clinical trial, a theoretical risk of ATEs exists following intravitreal use of VEGF inhibitors.

Serious adverse events related to the injection procedure occurring in less than 0.1% of intravitreal injections included endophthalmitis, rhegmatogenous retinal detachment, and iatrogenic traumatic cataract. Other serious ocular events occurring in less than 2% of patients included intraocular inflammation and increased IOP.

In clinical trials, the most common ocular adverse effects included conjunctival hemorrhage, eye pain, and vitreous floaters. The most common nonocular adverse effects included hypertension, nasopharyngitis, headache, and upper respiratory tract infection; none of which have been shown to be related to the drug. Aflibercept (Eylea; VEGF-Trap) is a soluble decoy receptor that binds VEGF and other vascular growth factors. It was approved by the FDA for the treatment of neovascular age-related macular degeneration (AMD) and other CNVs. 

In clinical trials, all aflibercept groups, including one group dosed only every two months, were noninferior and clinically equivalent to monthly ranibizumab for the primary endpoint (the 2q4, 0.5q4, and 2q8 regimens were 95.1%, 95.9%, and 95.1%, respectively, for VIEW 1, and 95.6%, 96.3%, and 95.6%, respectively, for VIEW 2, whereas monthly ranibizumab was 94.4% in both studies). In a prespecified integrated analysis of the 2 studies, all aflibercept regimens were within 0.5 letters of the reference ranibizumab for mean change in best corrected visual acuity (BCVA); all aflibercept regimens also produced similar improvements in anatomic measures. Ocular and systemic adverse events were similar across treatment groups. This led to the labelling of aflibercept for every-2-month administration after loading doses. Some medical retina experts suggest that aflibercept is more effective in patients with pigment epithelial detachments (PED). Clinical trials have shown that aflibercept is often effective in patients in whom ranibizumab or bevacizumab (Avastin) therapy has failed.

Bevacizumab is a larger anti-VEGF monoclonal antibody fragment that was originally developed to treat various types of cancer. Although unapproved by the FDA for treatment of CNV, monotherapy with bevacizumab is very effective and is widely used off-label for CNV not due to wet AMD.

Approximately 50% of retinal specialists use off-label bevacizumab instead of the FDA-approved ranibizumab or aflibercept, using a similar treatment schedule and indications for retreatment. The NEI-sponsored CATT trial was a head-to-head randomized multicenter comparison of ranibizumab to bevacizumab using with both monthly and PRN treatment arms. It revealed essentially no differences in efficacy, with a slightly higher number of adverse effects with bevacizumab.

Technique

Bevacizumab, ranibizumab, and aflibercept are administered through a fine 30- to 31-gauge needle, which most patients tolerate well.

A sterile intravitreal technique using povidone iodine; masks on the patient, tech and injecting physician; and a sterile bladed speculum are essential to reduce the risk of endophthalmitis.

Surgical Care

In 1991, Thomas and Kaplan reported a series of patients operated on for subfoveal CNVMs secondary to POHS.[62] Subsequent series included CNVM associated with AMD, angioid streaks, myopic degeneration, and idiopathic CNVM.[63, 64, 65] Idiopathic cases have the best results, followed by POHS cases. Most studies showed poor results for patients with AMD (approximately 20% had better vision, 60% had the same vision, and 20% had worse vision). Some surgeons state that submacular surgery for CNVM in patients with AMD may result in stabilization. Again, it must be emphasized that this procedure may also result in complete loss of vision, which is not true of the natural course of the disease. Results of the Submacular Surgery Trial (SST) demonstrated that submacular surgery is ineffective in AMD and POHS.

RPE transplantation has been used for patients with AMD by some investigators; 100% of patients undergo rejection of cadaver RPE, requiring immune suppression in those patients without a life-threatening disease.[66] Transplanted RPE cells do not become adherent to the Bruch membrane so the RPE cells would have to be transplanted as a sheet in combination with the Bruch membrane and probably choriocapillaris. Use of nasal RPE and iris pigment epithelium is not effective; neither support the macular visual cycle. Many biologic, practical, and ethical issues are associated with sourcing RPE cells for transplantation. RPE transplantation is not a viable therapy.[67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86]

Macular translocation has been advocated for subfoveal CNVM. One procedure uses vitrectomy, creation of a total retinal detachment, and a 360-degree retinotomy followed by retinal rotation. An alternate method, termed limited macular translocation, is based on retinal detachment creation and scleral imbrication or outpouching.[87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 41, 42, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 79, 80, 149, 150, 151, 36, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161]

Many eyes have been lost as a result of retinal translocation. Bleeding, retinal detachment, proliferative vitreoretinopathy (PVR), macular holes, new neovascular membranes, and good anatomical results without visual improvement are frequent complications of translocation.[162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173] Significant aniseikonia, high astigmatism, diplopia, enophthalmos, and ptosis are associated with limited macular translocation.[174, 175, 176, 177] Major cycloversion and diplopia are associated with retinal rotation methods.[178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188] Neither form of translocation has sufficient safety and efficacy to be indicated.

Consultations

In most cases, general ophthalmologists should consult retina specialists.

Diet

Eating spinach, kale, mustard greens, turnip greens, collard greens, nuts, and oily fish reduce the progression rate of patients with signs of early AMD. Berries and other plant-based diet elements rich in antioxidants are also probably effective. Patients may respond to suggesting a diet consisting of relative high quantities of richly colored vegetables and fruits, the so-called rainbow diet.

Activity

High blood pressure could theoretically result in bleeding from active neovascularization. Smoking increases the risk of AMD progression by 350-500%.

 

Medication

Anti-VEGF therapy

Class Summary

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

Pegaptanib (Macugen)

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.

 

Follow-up

Further Outpatient Care

Postsubmacular surgery patients require a first postoperative day visit, followed by a 2- to 3-week visit. Thereafter, any time that the patient notes a change in the Amsler grid, a visit should be scheduled.

Further Inpatient Care

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

Transfer

Retinal specialists should manage patients with CNVM.

Complications

Recurrent CNVMs occur in 25-50% of submacular surgery cases.

Cataracts occur frequently after vitreoretinal surgery.

Subretinal, suprachoroidal, and vitreous hemorrhage can occur after surgery.

Retinal detachment can occur after surgery.

Endophthalmitis can occur after any ocular surgery or intravitreal injection.

Steroid glaucoma occurs 20-30% of the time after intravitreal injection of Kenalog.

Prognosis

There is a 25-50% chance of recurrent CNVM after submacular surgery. Submacular hemorrhage is not uncommon after submacular surgery. Postoperative vision typically is limited by recurrences, damage to the RPE, and overlying retina.

Patient Education

Advise patients to use the Amsler grid to monitor their central fields daily.[189]

For excellent patient education resources, visit eMedicineHealth's Eye and Vision Center. Also, see eMedicineHealth's patient education article Macular Degeneration.