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Macular Degeneration, Age-Related

BASICS

DESCRIPTION

- Amsler grid testing - Fluorescein angiography - Detection of CNVMs - Differentiate between atrophic and neovascular ARMD.

  • Age-related macular degeneration (ARMD) results in pigmentary changes in the macula or typical drusen associated with visual loss to the 20/30 level or worse, not caused by cataract or other eye disease, in individuals >50 years of age, although some definitions exclude age or visual acuity criteria.
  • Leading cause of irreversible, severe visual loss in persons age >65 years
  • StagesAtrophic/nonexudativeNeovascular/exudative
  • System(s) affected: nervous
  • Synonym(s): senile macular degeneration; subretinal neovascularization

EPIDEMIOLOGY

  • Neovascular/exudative form is rare in blacks and more common in whites.
  • Predominant sex: female

Incidence

  • In the Framingham Eye Study (FES), drusen were noted in 25% of all participants who were ≥52 years of age. ARMD-associated visual loss was noted in 5.7%.
  • Atrophic/nonexudative stage accounts for 20% of cases of severe visual loss
  • Neovascular/exudative stage accounts for 80% of cases of severe visual loss

Prevalence

Per FES study: пїЅ пїЅ

  • People 65 to 74 years old: 11%
  • People ≥75 years old: 27.9%

ETIOLOGY AND PATHOPHYSIOLOGY

  • Breaks in the Bruch membrane allow choroidal neovascular membranes (CNVMs) to invade the retinal pigment epithelium (RPE) and grow into the subretinal space.
  • Atrophic/nonexudative: drusen and/or pigmentary changes in the macula
  • Neovascular/exudative: growth of blood vessels underneath the retina
  • Visible light can result in the formation and accumulation of metabolic by-products in the RPE, a pigment layer underneath the retina that normally helps remove metabolic by-products from the retina. Excess accumulation of these metabolic by-products interferes with the normal metabolic activity of the RPE and can lead to the formation of drusen.
  • Neovascular stage generally arises from the atrophic stage.
  • Most do not progress beyond the atrophic/nonexudative stage; however, those who do are at a greater risk of severe visual loss.

Genetics

  • Genetic susceptibility may be a factor in ARMD: пїЅ пїЅ пїЅ25% genetically determined.
  • Complement factor H is an important susceptibility gene for ARMD.
  • Although the development of ARMD may be predicted by specific alleles, the clinical response to antivascular endothelial growth factor is not (1)[A].

RISK FACTORS

  • Obesity
  • Ethnicity: non-Hispanic whites
  • Cigarette smoking
  • Chlamydia pneumoniae infection
  • Family history
  • Excess sunlight exposure
  • Blue or light iris color
  • Hyperopia
  • History of cardiovascular disease
  • Short stature
  • Aspirin use
  • Female sex

GENERAL PREVENTION

  • Ultraviolet (UV) protection for eyes
  • Routine ophthalmologic visitsEvery 2 to 4 years for patients age 40 to 64 yearsEvery 1 to 2 years after age 65 years
  • Patients who take statins, which modify lipid profiles, may have a reduced risk.

COMMONLY ASSOCIATED CONDITIONS

  • Presumed ocular histoplasmosis syndrome
  • Exudative retinal detachment
  • Vitreous hemorrhage
  • Other causes of CNVMs

DIAGNOSIS

HISTORY

  • Patients frequently notice distortion of central vision.
  • Patients may notice straight lines appear crooked (e.g., telephone poles).

PHYSICAL EXAM

  • Atrophic/nonexudative stage retinal examDrusen (small yellowish white lesions)Subtypes: hard drusen and soft drusenAtrophy of the RPE
  • Neovascular/exudative stage retinal examBlood vessels growing underneath the retina from the choroid are called CNVMs or subretinal neovascularization (SRN). The choroid is the vascular layer underneath the RPE.Subretinal fluid or hemorrhageExudatesOn Amsler grid testing, the horizontal or vertical lines may become broken, distorted, or missing.
  • Disciform scar: an advanced stage resulting in a fibrovascular scar

DIFFERENTIAL DIAGNOSIS

  • Idiopathic SRN
  • Presumed ocular histoplasmosis syndrome
  • Diabetic retinopathy
  • Hypertensive retinopathy

DIAGNOSTIC TESTS & INTERPRETATION

Diagnostic Procedures/Other

  • Amsler grid testing
  • Fluorescein angiographyDetection of CNVMsDifferentiate between atrophic and neovascular ARMD.
  • Indocyanine green video angiography: may identify occult or hidden CNVMs
  • Optical coherence tomography (OCT) may be useful in identifying CNVMs, subretinal fluid, and retinal thickening.Fluorescein angiography is better than time-domain OCT in detecting new-onset CNVMs

Test Interpretation

Drusen: deposits of hyaline material between the RPE and Bruch membrane (the limiting membrane between the RPE and the choroid) пїЅ пїЅ

TREATMENT

MEDICATION

First Line

  • Ranibizumab (Lucentis)Antibody fragment that inhibits all active forms of vascular endothelial growth factor (VEGF)Approved for neovascular (wet) ARMDInjected intravitreally, at a dose of 0.5 mg, every 4 weeks1 year after treatment, up to 40% of patients treated with ranibizumab gained at least three lines of vision and пїЅ пїЅ пїЅ95% maintained vision.Ranibizumab is superior to verteporfin in the treatment of predominately classic CNVMs.The PrONTO study demonstrated OCT-guided, variable-dosing regimen with ranibizumab resulted in similar results to the MARINA and ANCHOR studies with monthly injections.When comparing ranibizumab and bevacizumab in a multicenter study, both treatments were effective in stabilizing visual loss, and no difference was found in the visual outcome between the 2 treatment groups. A slightly higher rate of serious systemic adverse events was noted in the bevacizumab group (2)[A].In this study treatment as needed resulted in less gain in visual acuity, whether instituted at enrollment or after 1 year of monthly treatment.Eyes with ≥50% of the lesion composed of blood had a similar visual prognosis compared to other treated eyes in the Comparison of Age-related Macular Degeneration Treatmenst Trials (CATT). Neovascular ARMD lesions composed of >50% blood can be managed similarly to those with less or no blood (3)[A].The treat and extend regimen (TER) is commonly used to decrease the treatment burden. Once no signs of CNVM activity are detected, patient follow-ups and treatments are then extended by intervals of 2 weeks as long as no signs of CNVM activity are present, up to a maximum interval of 12 weeks. If examination shows any sign of recurrence, the interval is shortened by 2 weeks at a time, until the disease is considered to be inactive. Interval extension is then restarted, with the maximum final interval being 2 weeks less than the period when the previous recurrence was observed.Ranibizumab and bevacizumab had equivalent effects on visual acuity at 1 year using the TER. The visual acuity results at 1 year were comparable to those of other clinical trials with monthly treatment (4)[A]
  • VEGF Trap-Eye/aflibercept (Eylea)A decoy VEGF receptor that inhibits all isoforms of VEGF-A and placental growth factor (PlGF), the members of the VEGF family in mammals primarily involved in ocular neovascularizationApproved for neovascular (wet) ARMDInjected intravitreally, at a dose of 2 mg, every 4 weeks for 12 weeks then every 8 weeksDosed as needed after the 12-week fixed dosing schedule resulted in a 5.3-letter gain in best corrected visual acuity at 52 weeks (5)[B].Routine use of prophylactic antibiotics after intravitreal injections may be unnecessary (6)[B].Maybe beneficial in patients who are not responding to ranibizumab or bevacizumab (7)[C]

Second Line

  • Bevacizumab (Avastin) is a full-length antibody to VEGF, administered intravitreally at a dose of 1.25 mg; it is being evaluated in the treatment of neovascular ARMD. Widely used off-label because of its lower cost.
  • Agents that block platelet-derived growth factor (PDGF) are being investigated.

GENERAL MEASURES

Low-vision aids may be helpful. пїЅ пїЅ

SURGERY/OTHER PROCEDURES

  • Laser treatment for CNVMs located ≥200 microns from the center of the macula has been evaluated in the Macular Photocoagulation Study (MPS).Anti-VEGF treatment is first-line therapy for subfoveal CNVM 's.
  • Vitrectomy has been used to remove CNVMs, but this is generally not recommended.
  • CNVMs can bleed spontaneously, leaving blood underneath the retina. Vitrectomy to remove subretinal blood may be of benefit and should be performed within 7 days of the bleed. Tissue plasminogen activator (tPA) instilled into the eye, may help remove a subretinal hemorrhage. In some cases, intravitreal gas with or without tPA may displace submacular blood:Intravitreal anti-VEGF monotherapy may be helpful in the treatment of neovascular ARMD associated with a submacular hemorrhage (8)[C].
  • Photodynamic therapy (PDT) with verteporfin reduces vision loss in patients with >50% "classic " пїЅ subfoveal CNVMs. Verteporfin is administered IV, and a diode laser at 689 nm is applied to the CNVM.Patients should be informed of a <4% risk of acute, severe vision loss after PDT.Ranibizumab has greater clinical efficacy than PDT.Combination treatment with intravitreal ranibizumab and PDT appears to offer similar gain in visual acuity when compared with ranibizumab monotherapy (9)[B].Combination treatment with ranibizumab and PDT may reduce the number of ranibizumab retreatments.
  • Stereotactic radiotherapy is being investigated in the treatment of neovascular ARMD.
  • Laser photocoagulation to treat drusen is not recommended.

COMPLEMENTARY & ALTERNATIVE MEDICINE

Free radical formation in the retina, induced by visible light, may play a role in cellular damage that results in atrophic/nonexudative macular degeneration. The Age-Related Eye Disease Study (AREDS) found that a high-dose regimen of antioxidant vitamins and mineral supplements reduced progression of ARMD in some cases. пїЅ пїЅ

  • Recommended daily doses: vitamin C 500 mg, vitamin E 400 IU, пїЅ пїЅ-carotene 15 mg, zinc oxide 80 mg, and cupric oxide 2 mg
  • Exercise caution with пїЅ пїЅ-carotene use in smokers due to potential link to lung cancer.
  • The Age-Related Eye Disease Study 2 (AREDS2) found the addition of lutein with zeaxanthin alone or in combination with omega-3 fatty acids had no overall effect in further reducing the risk of progression to advanced ARMD (10)[A].

ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

Patient Monitoring

  • Amsler grid can aid in discovering visual disturbances.
  • Patients with soft drusen or pigmentary changes in the macula are at an increased risk of visual loss. They should monitor their vision, such as by daily Amsler grid testing, and subjective measures of visual acuity, such as reading ability. If no new symptoms, follow-up examination in 6 to 12 months

DIET

  • Eating dark green, leafy vegetables (spinach/collard greens), which are rich in carotenoids, may decrease the risk of developing the neovascular/exudative stage.
  • Fish consumption with omega-3 fatty acid intake reduces the risk of ARMD.
  • A Western type diet characterized by higher intake of red meat, processed meat, high-fat dairy products, French fries, refined grains, and eggs increases the risk of ARMD as compared to an Oriental type diet characterized by higher intake of vegetables, legumes, fruit, whole grains, tomatoes, and seafood which decreases the risk of ARMD (11)[A].

PATIENT EDUCATION

Instruct visually impaired patients to check with the local low-vision center for aids. пїЅ пїЅ

PROGNOSIS

  • Patients with bilateral soft drusen and pigmentary changes in the macula, but no evidence of exudation, have an increased likelihood of developing CNVMs and subsequent visual loss.
  • Patients with bilateral drusen carry a cumulative risk of 14.7% over 5 years of suffering significant visual loss in one eye from the neovascular stage of ARMD.
  • Patients with neovascular stage in one eye and drusen in the opposite eye are at an annual risk of 5 " пїЅ14% of developing the neovascular stage in the opposite eye with drusen.
  • High incidence of recurrence after thermal laser treatment for CNVMs

COMPLICATIONS

  • Blindness
  • The intraocular pressure should be monitored in eyes receiving intravitreal anti-VEGF injections.

REFERENCES

11 Hagstrom пїЅ пїЅSA, Ying пїЅ пїЅGS, Pauer пїЅ пїЅGJ, et al. Pharmacogenetics for genes associated with age-related macular degeneration in the Comparison of AMD Treatment Trials (CATT). Ophthalmology. 2013;120(3):593 " пїЅ599.22 Martin пїЅ пїЅDF, Maguire пїЅ пїЅMG, Fine пїЅ пїЅSL, et al. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results. Ophthalmology. 2012;119(7):1388 " пїЅ1398.33 Altaweel пїЅ пїЅMM, Daniel пїЅ пїЅE, Martin пїЅ пїЅDF, et al. Outcomes of eyes with lesions composed of >50% blood in the Comparison of Age-related Macular Degeneration Treatments Trials (CATT). Ophthalmology. 2015; 122(2):391.e5 " пїЅ398.e5.44 Berg пїЅ пїЅK, Pedersen пїЅ пїЅTR, Sandvik пїЅ пїЅL, et al. Comparison of ranibizumab and bevacizumab for neovascular age-related macular degeneration according to LUCAS treat-and-extend protocol. Ophthalmology. 2015; 122(1):146 " пїЅ152.55 Heier пїЅ пїЅJS, Boyer пїЅ пїЅD, Nguyen пїЅ пїЅQD, et al. The 1-year results of CLEAR-IT 2, a phase 2 study of vascular endothelial growth factor trap-eye dosed as-needed after 12-week fixed dosing. Ophthalmology. 2011;118(6):1098 " пїЅ1106.66 Yin пїЅ пїЅVT, Weisbrod пїЅ пїЅDJ, Eng пїЅ пїЅKT, et al. Antibiotic resistance of ocular surface flora with repeated use of a topical antibiotic after intravitreal injection. JAMA Ophthalmol. 2013;131(4):456 " пїЅ461.77 Chang пїЅ пїЅAA, Li пїЅ пїЅH, Broadhead пїЅ пїЅGK, et al. Intravitreal aflibercept for treatment-resistant neovascular age-related macular degeneration. Ophthalmology. 2014;121(1):188 " пїЅ192.88 Shienbaum пїЅ пїЅG, Garcia Filho пїЅ пїЅCA, Flynn пїЅ пїЅHWJr, et al. Management of submacular hemorrhage secondary to neovascular age-related macular degeneration with anti-vascular endothelial growth factor monotherapy. Am J Ophthalmol. 2013;155(6):1009 " пїЅ1013.99 Larsen пїЅ пїЅM, Schmidt-Erfurth пїЅ пїЅU, Lanzetta пїЅ пїЅP, et al. Verteporfin plus ranibizumab for choroidal neovascularization in age-related macular degeneration: twelve-month MONT BLANC study results. Ophthalmology. 2012;119(5):992 " пїЅ1000.1010 Age-Related Eye Disease Study 2 Research пїЅ пїЅGroup. Lutein + zeaxanthin and omega-3 fatty acids for age-related macular degeneration: the Age-Related Eye Disease Study 2 (AREDS2) randomized clinical trial. JAMA. 2013;309(19):2005 " пїЅ2015.1111 Chiu пїЅ пїЅCJ, Chang пїЅ пїЅML, Zhang пїЅ пїЅFF, et al. The relationship of major American dietary patterns to age-related macular degeneration. Am J Ophthalmol. 2014;158(1):118.e1 " пїЅ127.e1.

CODES

ICD10

  • H35.30 Unspecified macular degeneration
  • H35.32 Exudative age-related macular degeneration
  • H35.31 Nonexudative age-related macular degeneration

ICD9

  • 362.50 Macular degeneration (senile), unspecified
  • 362.52 Exudative senile macular degeneration
  • 362.51 Nonexudative senile macular degeneration

SNOMED

  • 267718000 Age-related macular degeneration (disorder)
  • 414173003 Exudative age-related macular degeneration
  • 414875008 Nonexudative age-related macular degeneration
  • 15633131000119109 Bilateral age-related exudative degeneration of macula (disorder)
  • 15633091000119107 Age-related exudative macular degeneration of left eye (disorder)
  • 15632971000119103 Age-related nonexudative macular degeneration of left eye (disorder)
  • 15633011000119103 Age-related nonexudative macular degeneration of right eye (disorder)
  • 15632931000119101 Bilateral age-related nonexudative macular degeneration (disorder)
  • 15633051000119102 Age-related exudative macular degeneration of right eye (disorder)

CLINICAL PEARLS

  • Patients frequently notice distortion of central vision.
  • Patients may notice straight lines appear crooked (e.g., telephone poles).
  • Hyperopia is a risk factor for ARMD.
  • The AREDS study found that a high-dose regimen of antioxidant vitamins and mineral supplements reduces progression of ARMD in some cases.
  • Tobacco cessation should be strongly encouraged.