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eMedicine Specialties > Ophthalmology > Retina

ARMD, Exudative

Grant M Comer, MD, Vitreoretinal Service, Clinical Ophthalmologist, Kellogg Eye Center, University of Michigan
Thomas Ciulla, MD, Associate Professor, Department of Ophthalmology, Indiana University School of Medicine; Mark H Criswell, PhD, Director of Retina Service Research Laboratories, Assistant Research Professor, Department of Ophthalmology, Indiana University School of Medicine; Alon Harris, PhD, Lois Letzter Professor, Director of Glaucoma Research and Diagnostic Center, Department of Ophthalmology, Indiana University School of Medicine

Updated: Jun 25, 2008

Introduction

Background

Types of macular degeneration

Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss in the industrialized world.1,2,3

Physicians have traditionally recognized two types of macular degeneration: dry and wet. The dry, or nonexudative, form involves both atrophic and hypertrophic changes of the retinal pigment epithelium (RPE) underlying the central macula, as well as drusen deposition beneath the RPE. Patients with nonexudative AMD can progress to the wet, or exudative, form of AMD, in which pathologic choroidal neovascular membranes (CNVM) develop under the retina, leak fluid and blood, and, ultimately, cause a centrally blinding disciform scar over a relatively short time course if left untreated. Approximately 10-20% of patients with nonexudative AMD eventually progress to the exudative form, which is responsible for the majority of the estimated 1.75 million cases of advanced AMD in the United States.4,5

In 1995, the International ARM Epidemiologic Study Group redefined AMD from the traditional wet and dry designations. The criteria for the diagnosis of AMD subsequently became stricter. Patients with minimal or moderate nonexudative age-related changes in the macula were reclassified as having age-related maculopathy (ARM). By definition, advanced RPE atrophy (ie, geographic atrophy) or choroidal neovascularization (CNV) was required to establish a diagnosis of nonexudative AMD and exudative AMD, respectively.6 An alternative classification scheme uses a 9-step severity scale to allow for risk stratification and reproducibility of age-related macular changes.7

As a result of the International ARM Epidemiologic Study Group efforts, patients with ARM account for 85-90% of individuals with age-related macular changes and have only mild drusen, RPE atrophy, and/or RPE hypertrophy. They tend to be asymptomatic or only minimally symptomatic with mild blurred central vision, color and contrast disturbances, and metamorphopsia (waviness). Conversely, the 10-15% of patients with macular changes defined as AMD tend to report painless, progressive, moderate-to-severe blurring of central vision and moderate-to-severe metamorphopsia, which can be acute or insidious in onset.

Pathophysiology

AMD is a degenerative retinal disease, presumably caused by both genetic and environmental factors. While age, race, and family history demonstrate a consistently strong association with AMD in large epidemiological studies, smoking, hypertension, and cataract surgery are also consistently reported modifiable risk factors contributing to the advancement of AMD.8

The exact pathophysiology of AMD is relatively poorly understood; however, recent discoveries in genetics have pointed toward the complement pathway as a primary mechanism. A strong association was discovered between AMD and a single nucleotide polymorphism in the complement factor H (CFH) gene on chromosome 19,10,8,11 and the PLEKHA1 and LOC387715 genes on chromosome 10.12   Conversely, protective effects were reported for polymorphisms in the complement factor B and complement component 2 genes on chromosome 6 and various haplotypes on the CFH gene.13,11

CFH is an inhibitor of the complement pathways; thus, abnormal CFH activity allows for complement cascade activation and subsequent inflammatory response to subretinal tissues.11 Drusen, which are found in AMD, have inflammatory components from the cascade pathway.14 In addition, smoking, which decreases levels of CFH, significantly increases the odds of developing AMD over nonsmokers with the CFH polymorphism.15,16 Similarly, the complement factor B and complement component 2 genes, which are usually involved in the activation of the complement cascade, could limit complement pathway activation with a protective polymorphism and, thus, minimize the degree of chronic inflammation.13

Frequency

United States

AMD is the leading cause of irreversible visual loss in the United States, with variable degrees of age-related macular changes occurring in more than 10% of the population aged 65-74 years and 25% of the population older than 74 years.17

Approximately 10-20% of patients with nonexudative AMD progress to the exudative form.4 As a result, severe vision loss in many of the 1.75 million individuals with advanced AMD is secondary to the effects of CNV from AMD.17,5

As the population of individuals older than 85 years increases an estimated 107% by the year 2020,18 the overall prevalence of advanced AMD (geographic atrophy and/or CNV) is expected to increase from 1.75 million individuals to 2.95 million individuals.5

Mortality/Morbidity

AMD leads to an increase in the rate of depression19,20 and frequent falls.21

Because many activities of daily living require functional central visual acuity, AMD decreases all aspects of the patient's quality of life, including the patient’s ability to drive independently.22

Race

Persons of Caucasian ancestry are far more likely to have late ARM and vision loss from AMD than those of African23 or Hispanic lineage.24 However, studies have failed to show consistent differences between those of Caucasian and Asian descent.25,26

Sex

Data from several large population-based studies, including the Beaver Dam study,27 the Third National Health and Nutrition Examination Survey,28 and the Framingham study29 have suggested that women are at increased risk for AMD compared with men.

Age

According to the International Classification System, AMD cannot be diagnosed in patients younger than 50 years.6 Nearly every large population-based study has shown a positive correlation between the prevalence, incidence, and progression of AMD with increasing age.30,27,31,32,5

Clinical

History

Patients with ARM are often asymptomatic or sometimes notice mild symptoms, including minimally blurred central visual acuity, contrast and color disturbances, and mild metamorphopsia. If geographic atrophy develops in the macular region, patients may notice a scotoma (blind spot), which can slowly enlarge over months to years before eventually stabilizing.

Patients with exudative AMD typically describe painless progressive blurring of their central visual acuity, which can be acute or insidious in onset. Patients who develop subretinal hemorrhage from CNV, for example, typically report an acute onset. Other patients with CNVM may experience insidious blurring secondary to shallow subretinal fluid or pigment epithelial detachments (PEDs). They also report relative or absolute central scotomas, metamorphopsia, and difficulty reading.

The natural history of exudative AMD or occasionally nonexudative AMD results in a stable central scotoma in which the visual acuity falls below the reading level and the legal driving level. However, peripheral visual acuity is usually retained.

Physical

AMD occurs bilaterally, but it is often asymmetric. Visual acuity is variably reduced. Amsler grid testing typically reveals relative central scotomas or metamorphopsia.

The sine qua non of exudative AMD is CNVM. Eyes with exudative AMD present with subretinal fluid, retinal PEDs, subretinal hemorrhage, and, occasionally, subretinal lipid deposits. In addition, RPE hypertrophy, RPE atrophy, and drusen are usually present. The CNV itself may be seen as yellow-green subretinal discoloration and is sometimes surrounded by a pigment ring. Subretinal hemorrhage typically develops at the margins of the CNV and sometimes obscures the entire complex. On occasion, the subretinal hemorrhage can progress and lead to vitreous hemorrhage. Subretinal disciform scarring of the macula is a common end-stage morphology.

Causes

In addition to age (see Age), strong risk factors include the following:  family history,33,10 Caucasian race,8 and a history of tobacco use.34,35

Other risk factors reported fairly consistently include hypertension and cataract surgery.8

Differential Diagnoses

Angioid Streaks
Neovascular Membranes, Subretinal
ARMD, Nonexudative
Neovascularization, Choroidal
Chorioretinopathy, Central Serous
Presumed Ocular Histoplasmosis Syndrome
Choroidal Rupture
Retinal Detachment, Exudative
Melanoma, Choroidal
Multifocal Choroidopathy Syndromes

Other Problems to Be Considered

Myopic degeneration
Polypoidal choroidal vasculopathy
Basal laminar drusen with vitelliform macular detachment
Parafoveal telangiectasis

Workup

Laboratory Studies

No laboratory studies assist in the diagnosis of AMD.

Imaging Studies

After a thorough dilated examination of the fundus with slit lamp biomicroscopy, stereo color photography of the fundus, rapid-sequence fluorescein angiography (FA), and optical coherence tomography (OCT) are performed on many patients with signs and symptoms of exudative AMD.

FA is an office-based procedure to help identify and confirm the source of the CNV. During the procedure, fluorescein dye is injected intravenously and serial photographs of the retina are taken to document the progression of the dye through the choroidal and retinal vasculature. Abnormalities are identified in areas where the dye collects (hyperfluorescence) or is absent (hypofluorescence).

Findings on FA consistent with exudative AMD include the following: increasing hyperfluorescence secondary to dye leakage from the CNV and hypofluorescent blockage from subretinal hemorrhage. Additional findings consistent with any form of AMD include the following: hyperfluorescence of drusen and RPE atrophy and hypofluorescence from RPE hypertrophy. A disciform scar, which is the end stage of exudative AMD, is hyperfluorescent from fluorescein staining.

  • Depending on the distance from the foveal avascular zone, the leakage is classified as subfoveal, juxtafoveal (1-199 µm), or extrafoveal (200-250 µm).
  • CNV is sometimes defined as classic or occult based on the FA leakage pattern.
    • Classic CNV results in discrete and early hyperfluorescence with late leakage of fluorescein dye into the surrounding interstitial spaces.
    • Occult CNV is categorized into 2 basic forms, as follows: late leakage of undetermined source or fibrovascular PED. Both forms manifest as a region of ill-defined leakage in the early and late frames without a distinct source of leakage.
  • When a treatment other than a vascular endothelial growth factor (VEGF) inhibitor is planned, angiography is customarily performed within 72 hours of treatment because the morphology and resulting treatment parameters can evolve rapidly.

Indocyanine green (ICG) angiography can be performed as an adjunctive study in patients with subretinal hemorrhage, suspected retinal angiomatous proliferation, or polypoidal choroidal vasculopathy.

  • The near-infrared light (795-810 nm) absorbed by ICG tends to penetrate hemorrhage and RPE better than the shorter wavelength that is absorbed by fluorescein.
  • Unlike fluorescein, ICG is strongly bound to plasma proteins, which prevents diffusion of the compound through the normally fenestrated choroidal capillaries and improves delineation of choroidal detail.

Optical coherence tomography (OCT) is a useful noninvasive adjunct for identifying retinal and subretinal pathology secondary to CNV.

  • OCT provides a cross-sectional view of the retina with an axial resolution of about 10 µm. (Newer versions report a resolution to about 4 µm with 3-D capabilities.)
  • OCT can identify soft drusen, RPE detachments, subretinal and intraretinal fluid, CNV, and cystoid macular edema.36,37,38
  • OCT is useful for monitoring the therapeutic response to photodynamic therapy (PDT) and anti-VEGF therapy.39,38,40

Treatment

Medical Care

Laser treatments

Thermal laser photocoagulation

Ophthalmologists have traditionally used thermal laser destruction of CNV as the primary treatment of exudative AMD based on the results of the Macular Photocoagulation Study (MPS). This study, which was initiated in the 1980s and supported by the National Institutes of Health, demonstrated that laser photocoagulation of extrafoveal, juxtafoveal, and subfoveal CNV limited the risk of severe reductions in visual acuity compared with observation alone.

Patients were eligible for laser photocoagulation if they had classic CNV, as determined by FA. However, only 13-26% of all patients with exudative AMD presented with this inclusion pattern. Therefore, it was unclear whether laser photocoagulation was beneficial to a majority of patients with exudative AMD.41,42,43,44,45,46 Moreover, at least one half of the enrolled subjects had persistent or recurrent CNV within 2 years of treatment.42,43

Today, thermal laser photocoagulation is usually reserved for CNV outside the fovea and for treatment of the variants of exudative AMD, including retinal angiomatous proliferation (RAP) and polypoidal choroidal vasculopathy.14,47 Although data from the subfoveal CNV arm of the MPS suggested that laser photocoagulation was better than observation, most clinicians do not treat subfoveal CNV with thermal photocoagulation because of the induction of an immediate, iatrogenic, central scotoma.43,44  Researchers have searched for alternative methods of treating subfoveal CNV with laser, including feeder-vessel photocoagulation48 and transpupillary thermotherapy49 ; however, these methods are not widely used clinically.

Photodynamic therapy

To avoid creating a central blinding scotoma when treating subfoveal CNV with thermal laser, clinicians turned to PDT. After intravenous infusion of a photosensitizing dye and a sufficient delay to concentrate it into pathologic choroidal neovascular tissue, the photosensitizer is stimulated with a specific wavelength of light focused through the pupil to it within the CNV. The dye reacts with water to create oxygen and hydroxyl free radicals, which, in turn, induce occlusion of the pathologic vasculature by means of massive platelet activation and thrombosis while preserving the normal choroidal vasculature and nonvascular tissue.50,51,52

Verteporfin therapy

In April 2000, the US Food and Drug Administration (FDA) approved PDT with verteporfin (Visudyne; QLT Therapeutics, Inc, Vancouver, British Columbia, Canada, and Novartis Ophthalmics, Bulach, Switzerland) for use in patients with predominantly classic, subfoveal CNV caused by AMD. Marketing approval was granted in Europe in July 2000, and the drug is currently commercially available in more than 70 countries for the treatment of predominantly classic CNV.53

Verteporfin is a modified porphyrin with an absorption peak near 689 nm that is delivered intravenously for 10 minutes. After a 5-minute delay, the CNV complex is irradiated through the pupil with a large-spot diode laser at 689 nm for 83 seconds. The laser energy activates the intravascular photosensitizer and stimulates the photodynamic action within the pathologic CNV. Verteporfin is cleared rapidly from the body, resulting in minimal skin sensitivity by 5 days.

In 2001, the 2-year results of the Treatment of AMD with PDT (TAP) trial were published. TAP consisted of 2 randomized, prospective, double-blind, placebo-controlled phase III trials with 609 subjects. Second-year data showed that 59% of treated eyes lost less than 15 letters on a standardized eye chart compared to 31% in the control group when the lesion was predominantly classic.19 The TAP trial was unmasked after 2 years of follow-up, and investigators continued with an open-label extension (to 36 mo) in 124 of the 159 original TAP participants with predominantly classic CNV. The data revealed that visual acuity remained nearly constant and the number of required repeat treatments decreased.54

Although standard PDT with verteporfin has shown promise in treating some forms of CNV, it is expensive, typically slows vision loss rather than improves it, and requires numerous repeat treatments. Therefore, other interventions to treat subfoveal CNV membranes were developed.

Antiangiogenic agents

VEGF inhibitors

Animal and clinical studies have established VEGF as a key mediator in ocular angiogenesis.55,56 In clinical trials, particular attention has focused on the development of pharmaceutical agents to block or neutralize VEGF expression.

Pegaptanib sodium

Pegaptanib sodium (Macugen; OSI Pharmaceuticals, Inc, Melville, NY and Pfizer, Inc, New York, NY) is an anti-VEGF pegylated aptamer that demonstrated both safety and efficacy in clinical trials compared to placebo. This intravitreally administered polyethylene glycol (PEG)–conjugated oligonucleotide was specifically designed to bind and neutralize VEGF165, hypothesized to be the predominant VEGF isomer associated with CNV in humans.

The VEGF Inhibition Study in Ocular Neovascularization (VISION) Study was comprised of 2 phase II-III multicenter, randomized, placebo-controlled trials. Enrollment of 1186 subjects was completed in July 2002. The 12-month data for all types of CNV showed that 70% of subjects receiving a 0.3-mg intravitreous injection every 6 weeks lost less than 3 lines of vision versus 55% of control subjects receiving sham injection (P <0.001),57 which is a similar efficacy to PDT.

The FDA accepted a new drug application (NDA) for wet AMD in August 2004, as did the European Medicines Agency (EMEA) in September 2004.58 On December 17, 2004, the FDA approved the drug, which became available for consumer use in the United States in January 2005.59

Ranibizumab

Ranibizumab (Lucentis; Genentech Inc, South San Francisco, CA, and Novartis Ophthalmics, Basel, Switzerland), an intravitreally injected, recombinant, humanized, monoclonal antibody fragment designed to actively bind and inhibit all isoforms of VEGF, has become a common treatment for exudative AMD.

The Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab (formerly, RhuFab) in the Treatment of Neovascular AMD (MARINA) was a phase III randomized, prospective, double-blind, placebo-controlled comparison of ranibizumab against sham controls. Investigators enrolled 716 patients to receive 24 monthly intravitreal injections (0.3 mg or 0.5 mg) or sham injections. At 12-month follow-up, 95% of those treated with monthly ranibizumab injections had improved or stable vision versus 62% of control subjects receiving sham treatment (P <0.001). More importantly, 34% of participants receiving the 0.5-mg dose experienced at least a 15-letter improvement that was maintained over 2 years (P <0.001).40

The Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in AMD (ANCHOR) trial was another prospective, randomized, multicenter, double-blind phase III trial designed to compare ranibizumab versus verteporfin in 423 subjects with predominantly classic exudative AMD. Similar to MARINA, 96% of subjects receiving 0.5 mg of ranibizumab had improved or stable vision versus 64% receiving verteporfin (P <0.001). Visual acuity improved in 40% of subjects receiving the 0.5-mg dose versus 6% in the verteporfin group (P <0.001).60

These trials altered the treatment paradigm of exudative AMD from a condition in which vision loss could only be slowed or stabilized to one in which visual acuity improvement was a real possibility. Clinicians are now attempting to maximize visual acuity while minimizing the number of retreatments to eyes with exudative AMD. The PIER trial gave 3 monthly injections of ranibizumab followed by quarterly injections over a 24-month interval. The 3-month results mirrored MARINA and ANCHOR; however, visual acuity gains declined once quarterly dosing began. The PIER data suggest that quarterly injections are less effective than monthly dosing.61

A newer approach is based on the Prospective OCT Imaging of Patients with Neovascular AMD Treated with Intra-Ocular Lucentis (PrONTO) Study, a small, uncontrolled open-label study, that treated patients with 3 monthly ranibizumab injections followed by monthly follow-up and redosing on an as-needed basis. The visual acuity improvements remained near the level of MARINA and ANCHOR, but the average number of retreatments dropped to 5.6 over 12 months.62 Other clinicians are adopting the "treat and extend" approach, where patients are treated with 3 serial monthly ranibizumab injections followed by gradually extending the interval between subsequent injections until fluid reaccumulates. If a time pattern of recurrence develops, tailored treatments can be adopted.

Bevacizumab
Prior to the commercial availability of ranibizumab, bevacizumab (Avastin, Genentech Inc, South San Francisco, CA) was attempted as an off-label VEGF inhibitor to control exudative AMD. Bevacizumab is a full-length humanized monoclonal antibody against human VEGF, whereas ranibizumab is a fragmented humanized monoclonal antibody against human VEGF. The FDA approved bevacizumab for the treatment of metastatic colorectal cancer on February 26, 2004.63

Researchers initiated the Systemic Avastin for Neovascular ARMD (SANA) Study, an open-label uncontrolled pilot study of 9 subjects with subfoveal CNV, to evaluate the efficacy of systemic intravenous bevacizumab. Patients were infused with 5 mg/kg bevacizumab every 2 weeks for 2-3 treatments. Follow-up through 12 weeks revealed significant improvements in mean visual acuity (P = 0.008) and central retinal thickness (P = 0.001) over baseline with a marked reduction in leakage on FA.64

To allay concerns about systemic morbidity, an intravitreal injection route was detailed in a case report in 2005 that demonstrated marked reduction of subretinal fluid and stable visual acuity.65 Numerous small studies have subsequently supported the use of intravitreal bevacizumab by demonstrating decreased retinal thickness and improved visual acuity over baseline.66,67,68,69,70  

Because ranibizumab ($1950/dose) and bevacizumab ($50-75/dose) have an enormous price differential, yet, as many retina physicians feel, comparable effectiveness, a great deal of interest exists in comparing the 2 medications directly. The National Eye Institute has recently funded a large randomized controlled trial to directly compare the safety and efficacy of bevacizumab and ranibizumab in the Comparison of Age-Related Macular Degeneration Treatment Trials (CATT) that is expected to begin enrollment in early 2008 and be completed by 2011 (www.clinicaltrials.gov, CATT study).

Combination therapies

Several clinical researchers have performed a variety of treatment combinations in attempting to maximize visual acuity recovery while minimizing the number of retreatments in exudative AMD.71,72  Larger randomized clinical trials are currently underway, including trials combining Visudyne PDT/VEGF inhibitor (LUV Trial, DENALI, MONT BLANC), Visudyne PDT/VEGF inhibitor/corticosteroid (RADICAL, TAPER), and Visudyne PDT/corticosteroid (VERITAS).

Surgical Care

Vitreoretinal surgeons have attempted to remove CNVM with direct surgical excision of the CNV complex. In 1998, the National Eye Institute of the National Institutes of Health awarded funding to the Submacular Surgery Trial (SST).
 
This study was a large randomized clinical trial comparing submacular CNVM removal versus observation. Patients were followed for 2 years and assessed for stabilization or deterioration of their visual acuity, a change in contrast sensitivity, cataract development, surgical complications, and quality of life. The trials did not demonstrate significant benefit of submacular surgery over observation.73,74

Medication

Visudyne for PDT of subfoveal, predominantly classic CNVM was approved in 2000, as outlined Medical Care. 

Ranibizumab (Lucentis) was approved by the FDA in 2006.

In addition, various experimental protocols (eg, antiangiogenic agents) are currently under investigation; some of these are outlined in Medical Care. 

Phototherapy agents

These agents are used for PDT in cases of subfoveal, predominantly classic CNV membranes.


Verteporfin (Visudyne)

Benzoporphyrin derivative monoacid (BPD-MA), consisting of equally active isomers BPD-MAC and BPD-MAD, which can be activated by low-intensity, nonthermal light of 689-nm wavelength. After activation and with oxygen, forms cytotoxic oxygen free radicals and singlet oxygen, which damages biologic structures in range of diffusion, leading to local vascular occlusion, cell damage and cell death.
Phase III data from the Treatment of Age-Related Macular Degeneration with Photodynamic Therapy Study Group showed that 61% of 402 eyes treated lost <15 letters of visual acuity at 12 mo vs 46% of 207 eyes receiving placebo (P <.001). In subgroup analysis, visual-acuity benefit persisted (67% vs 37%, P <.001) when CNV membrane was predominantly classic (50% or more of area of entire complex). Visual acuity not significantly different when the area of classic CNV membranes <50% entire complex. Patients needed mean of about 3 treatments in first y. At most recent follow-up, patients needed mean of 5 treatments in first 2 y.

Dosing

Adult

Administered IV with dose based on body mass index (BMI)

Pediatric

Not applicable; AMD cannot be diagnosed in patients <50 y

Interactions

None reported; many drugs can influence effect; theoretic examples include concomitant use of other photosensitizer (eg, tetracycline, sulfonamide, phenothiazine, sulfonylurea, hypoglycemic substances, thiazide diuretics, griseofulvin) can increase photosensitivity; compounds that scavenge active oxygen species or radicals (eg, dimethylsulphoxide, beta beta-carotene, ethanol, formate, mannitol) can reduce activity; calcium channel blockers, polymyxin B, or radiation therapy can increase rate of uptake by vascular endothelium; anticoagulants, vasoconstrictors, or platelet-aggregation inhibitors (eg, thromboxane-A2 inhibitors) can reduce effectiveness

Contraindications

Documented hypersensitivity; patients with porphyria

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Patients photosensitive to sunlight and strong artificial light for >48 h after infusion; wearing sunglasses and long-sleeved clothing highly recommended to avoid serious skin and eye burns; indoor lighting generally safe and recommended over complete darkness because accelerates breakdown of active drug; caution in advanced liver disease; extravasation can cause severe pain, inflammation, swelling, and discoloration at the injection site; cold compresses and analgesia helpful to reduce pain and complications of extravasation

Anti-VEGF therapy

This treatment reduces the risk of visual loss similar to that seen with PDT.


Pegaptanib (Macugen)

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 wet AMD

Dosing

Adult

0.3 mg injected intravitreally into affected eye q6wk

Pediatric

Not established

Interactions

None reported

Contraindications

Ocular or periocular infections

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Intravitreous injections associated with endophthalmitis; use proper aseptic technique; may increase intraocular pressure; most frequent adverse effects (10-40% patients over 24 mo) include anterior chamber inflammation, blurred vision, cataract, conjunctival hemorrhage, corneal edema, eye discharge, eye irritation, eye pain, hypertension, ocular discomfort, punctate keratitis, reduced visual acuity, visual disturbance, vitreous floaters, and vitreous opacities


Ranibizumab (Lucentis)

Recombinant humanized IgG1-kappa isotype monoclonal antibody fragment designed for intraocular use. Indicated for neovascular (wet) AMD. In clinical trials, about one third of patients had improved vision at 12 mo that was maintained by monthly injections. Binds to VEGF-A, including biologically active, cleaved form (ie, VEGF110). VEGF-A has been shown to cause neovascularization and leakage in ocular angiogenesis models and is thought to contribute to AMD disease progression. Binding VEGF-A prevents interaction with its receptors (ie, VEGFR1, VEGFR2) on surface of endothelial cells, thereby reducing endothelial cell proliferation, vascular leakage, and new blood vessel formation.

Dosing

Adult

0.5 mg (0.05 mL) intravitreal injection every month; administer under controlled, aseptic conditions

Pediatric

Not indicated

Interactions

Data limited; none reported

Contraindications

Documented hypersensitivity; ocular or periocular infection

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Common adverse effects include conjunctival hemorrhage, eye pain, floaters, increased eye pressure, and inflammation; serious adverse events were rare in clinical trials and were often related to injection procedures (eg, endophthalmitis, intraocular inflammation, retinal detachment, retinal tear, increased ocular pressure, traumatic cataract); may cause arterial thromboembolic events; administer anesthesia and antibiotic prophylaxis prior to procedure; prepare dose as directed using 5-micrometer filter

Follow-up

Patient Education

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

Multimedia

Age-related macular degeneration (AMD), exudative.

Media file 1: Age-related macular degeneration (AMD), exudative.

Age-related macular degeneration (AMD), exudative.

Media file 2: Age-related macular degeneration (AMD), exudative.

Color photograph of the fundus shows nonexudative...

Media file 3: Color photograph of the fundus shows nonexudative age-related macular degeneration (AMD) with geographic atrophy of the retinal pigment epithelium (RPE) and drusen. Absolute atrophy of the RPE occupies the foveal region in this case of nonexudative AMD. The central atrophic region causes a corresponding central scotoma. Note the large choroidal vessels, which are visible through the RPE defect. Drusen surround the region of geographic atrophy. Photo by Tim Steffens.

Late-frame fluorescein angiogram shows nonexudati...

Media file 4: Late-frame fluorescein angiogram shows nonexudative age-related macular degeneration (AMD) with geographic atrophy of the retinal pigment epithelium (RPE) and drusen from the case of geographic atrophy illustrated in Media file 3. Geographic atrophy stains intensely with distinct borders, but no leakage is present to suggest a choroidal neovascular membrane (CNVM). Stain highlights the large choroidal vessels in the region of atrophy well. Photo by Tim Steffens.

Color photograph of the fundus shows classic chor...

Media file 5: Color photograph of the fundus shows classic choroidal neovascular membrane (CNVM) causing subretinal hemorrhage. Subretinal hemorrhage, which resulted from a classic CNVM, occupies the foveal region, causing a dense central scotoma. The subretinal hemorrhage can be large, mimicking a choroidal melanoma. On occasion, the subretinal hemorrhage can break through the retina, causing a vitreous hemorrhage. Patients who present with vitreous hemorrhage and evidence of age-related macular degeneration (AMD) in the other eye should be thought to have a CNVM, especially if they have no history of diabetes or other causes of vitreous hemorrhage. Photo by Tim Steffens.

Midframe from the fluorescein angiogram of the ca...

Media file 6: Midframe from the fluorescein angiogram of the case in Media file 5 reveals the discrete region of hyperfluorescence, which is characteristic of a classic choroidal neovascular membrane (CNVM). Late frames of the angiogram (not shown) revealed intense leakage from the CNVM. Subretinal hemorrhage is more commonly due to classic CNVM than occult CNVM and typically occurs along the peripheral aspect of the CNVM. Photo by Tim Steffens.

Midframe fluorescein angiogram shows classic plus...

Media file 7: Midframe fluorescein angiogram shows classic plus occult choroidal neovascular membrane (CNVM). Temporal to the foveal region, image reveals a discrete region of hyperfluorescence that is suggestive of a classic CNVM. Photo by Tim Steffens.

Late-frame fluorescein angiogram shows classic pl...

Media file 8: Late-frame fluorescein angiogram shows classic plus occult choroidal neovascular membrane (CNVM). Late frames of the angiogram from the case in Media file 7 show leakage from the discrete focus (seen in early frames). This finding is characteristic of the classic component. The surrounding late-stippled leakage is characteristic of the occult component. Photo by Tim Steffens.

Color photograph of the fundus shows a retinal pi...

Media file 9: Color photograph of the fundus shows a retinal pigment epithelium (RPE) tear. The RPE has torn from the nasal portion of the macula and assumed a scrolled, redundant configuration in the temporal portion of the macula. Associated sub-RPE and subretinal hemorrhage is present, as are hard exudates and subretinal fluid. Courtesy of Albert R. Frederick, Jr, MD.

Early-frame fluorescein angiogram shows a retinal...

Media file 10: Early-frame fluorescein angiogram shows a retinal pigment epithelium (RPE) tear. Fluorescein angiogram from the case illustrated in Media file 9 temporally shows blockage of the choroidal flush by the redundant, scrolled RPE. Stained areas represent where the RPE was torn. Later frames of the angiogram (not shown) also showed leakage due to the associated choroidal neovascular membrane (CNVM). Courtesy of Albert R. Frederick, Jr, MD.

Late-frame fluorescein angiogram. Classic choroid...

Media file 11: Late-frame fluorescein angiogram. Classic choroidal neovascular membrane (CNVM) before laser photocoagulation shows classic CNVM, which manifests as a discrete, early focus of hyperfluorescence with late leakage. Associated subretinal hemorrhage at the peripheral edge of the CNVM blocks the underlying choroidal flush. Photo by Tim Steffens.

Early-frame fluorescein angiogram shows classic c...

Media file 12: Early-frame fluorescein angiogram shows classic choroidal neovascular membrane (CNVM) after laser photocoagulation. Classic CNVM illustrated in Media file 11 was photocoagulated. The patient underwent repeat fluorescein angiography (image shown here) 2 weeks later to rule out persistence. Note nonperfusion of the choriocapillaris and CNVM in the laser scar. Photo by Tim Steffens.

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Keywords

exudative ARMD, age-related macular degeneration, AMD, age-related maculopathy, ARM, macular degeneration, choroidal neovascularization, choroidal neovascular membrane, CNVM, CNV, vision loss

Contributor Information and Disclosures

Author

Grant M Comer, MD, Vitreoretinal Service, Clinical Ophthalmologist, Kellogg Eye Center, University of Michigan
Grant M Comer, MD is a member of the following medical societies: American Academy of Ophthalmology, Michigan Society of Eye Physicians & Surgeons, and Phi Beta Kappa
Disclosure: Nothing to disclose.

Coauthor(s)

Thomas Ciulla, MD, Associate Professor, Department of Ophthalmology, Indiana University School of Medicine
Thomas Ciulla, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Ophthalmology, and Association for Research in Vision and Ophthalmology
Disclosure: Nothing to disclose.

Mark H Criswell, PhD, Director of Retina Service Research Laboratories, Assistant Research Professor, Department of Ophthalmology, Indiana University School of Medicine
Mark H Criswell, PhD is a member of the following medical societies: Association for Research in Vision and Ophthalmology
Disclosure: Nothing to disclose.

Alon Harris, PhD, Lois Letzter Professor, Director of Glaucoma Research and Diagnostic Center, Department of Ophthalmology, Indiana University School of Medicine
Alon Harris, PhD is a member of the following medical societies: American College of Sports Medicine, American Physiological Society, American Society for Laser Medicine and Surgery, and New York Academy of Sciences
Disclosure: Nothing to disclose.

Medical Editor

Brian A Phillpotts, MD, Former Vitreo-Retinal Service Director, Former Program Director, Clinical Assistant Professor, Department of Ophthalmology, Howard University College of Medicine
Brian A Phillpotts, MD is a member of the following medical societies: American Academy of Ophthalmology, American Diabetes Association, American Medical Association, and National Medical Association
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Steve Charles, MD, Director of Charles Retina Institute; Clinical Professor, Department of Ophthalmology, University of Tennessee College of Medicine
Steve Charles, MD is a member of the following medical societies: American Academy of Ophthalmology, American Society of Retina Specialists, Club Jules Gonin, Macula Society, and Retina Society
Disclosure: Alcon Laboratories Consulting fee Consulting; OptiMedica Ownership interest Consulting

CME Editor

Lance L Brown, OD, MD, Ophthalmologist, Affiliated With Freeman Hospital and St John's Hospital, Regional Eye Center, Joplin, Missouri
Disclosure: Nothing to disclose.

Chief Editor

Hampton Roy Sr, MD, Associate Clinical Professor, Department of Ophthalmology, University of Arkansas for Medical Sciences
Hampton Roy Sr, MD is a member of the following medical societies: American Academy of Ophthalmology, American College of Surgeons, and Pan-American Association of Ophthalmology
Disclosure: Nothing to disclose.

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