Macular Degeneration

Age-related macular degeneration (AMD) is visual impairment due to changes in the macula, the area responsible for high-acuity vision. It is marked by central vision loss with peripheral vision relatively spared. Risk factors include advanced age, smoking, family history, and cardiovascular disease. The 2 types of AMD are exudative (wet) or non-exudative (dry). The difference between these 2 types is the presence of choroidal neovascularization in wet AMD, which manifests as visual distortion or loss. The more frequently occurring dry AMD is usually asymptomatic but in a minority of cases leads to vision loss. There is no treatment for early dry AMD but Age-Related Eye Disease Study 2 (AREDS 2) supplements are recommended for advanced disease. Inhibitors of vascular endothelial growth factor are used for wet AMD.

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Overview

Definition

Age-related macular degeneration (AMD):

  • Degenerative changes involving the macula, the central part of the retina, that cause central vision impairment
  • Often affects bilateral vision, but can be asymmetrical
  • Peripheral vision is rarely lost.

Anatomy

  • Macula: 
    • An oval area at the center of the retina, where light is focused by the lens and cornea
    • Contains the fovea, which holds the highest density of cone cells (photoreceptors sensitive to colors under bright light conditions)
    • Function: 
      • Central, high-acuity, and color vision
      • Provides the ability to read, drive, and see in great detail 
  • Other structures:
    • Photoreceptor cells in outer retina: light-sensing rods and cones
    • Retinal pigment epithelium (RPE)
      • Protects from damaging effects of sunlight
      • Eliminates waste products and damaged cells
      • Regulates transport of nutrients
    • Bruch’s membrane:
      • Barrier and filter separating the retina from blood vessels
      • A defect can be a site of blood vessel growth.
    • Capillary bed in the inner choroid (choriocapillaris): 
      • Nourishment and oxygen to RPE and outer layers of the retina 
      • Main blood supply for fovea

Classification

  • Dry AMD (non-exudative or atrophic)
    • 90% of all cases
    • Often asymptomatic with gradual onset of visual changes 
    • In a minority of patients: advances to central visual-field loss or wet AMD
    • Associated with drusen:
      • Deposits of extracellular material or waste beneath the RPE
      • Few are found in people > 50 years old as part of aging.
    • Increased size and/or number of drusen → AMD
  • Wet AMD (exudative or neovascular)
    • 10% of cases but accounts for majority of patients with advanced AMD
    • Presents as insidious or rapid progression of central vision loss
  • Caused by growth of abnormal blood vessels in the subretinal space, frequently from the choroidal circulation (choroidal neovascularization (CNV))

Epidemiology

  • The leading cause of  irreversible blindness in developed countries
  • Worldwide prevalence of 8.7%
  • Women are affected more than men. 
  • Risk factors:
    • Advanced age: ↑ incidence in > 60 years of age
    • Caucasians > African Americans or Hispanics
    • Smoking 
    • Heavy alcohol use (> 3 drinks per day)
    • Family history 
    • Genetic predisposition (complement H gene)
    • Obesity
    • Hypercholesterolemia
    • Cardiovascular disease
    • HIV/AIDS
    • Chronic myeloproliferative disease
    • Cataract surgery
  • Decrease the risk of AMD: ↑ fish intake, ↑ omega-3, and omega-6 polyunsaturated fatty acids

Pathophysiology

Dry AMD

  • Exact mechanism is still unclear.
  • Known risk factors (such as aging and genetics), oxidative stress, and inflammation lead to pathologic changes:
    • Aging Bruch’s membrane: membrane thickens and accumulates apolipoproteins → ↑ inflammation and debris  →  nodular basal deposits become soft drusen
    • RPE degeneration → dissociates from Bruch’s membrane → RPE dysfunction → photoreceptor loss
    • Loss of choriocapillaris:  
      • Correlates with ↑ size and number of soft drusen 
      • Precedes the damage of RPE (geographic atrophy)

Wet AMD

  • Risk factors + oxidative stress + activated complement → inflammatory changes 
  • Inflammation → RPE and other retinal cells secrete vascular endothelial growth factor (VEGF)-A and vasculogenic molecules → CNV and RPE dysfunction
  • New immature blood vessels grow from the choroid → perforate Bruch’s membrane and extend toward the retina
  • These blood vessels leak fluid and blood below or within the retina → RPE detachment and hemorrhage

Clinical Presentation

Dry AMD

  • Symptoms
    • Asymptomatic in most cases
    • As disease progresses:
      • Difficulty with night vision
      • Visual fluctuation
      • Reading difficulty
      • Cannot make out faces
      • Prolonged time to adapt to low light levels
      • Metamorphopsia (distorted straight lines) in advanced disease
  • Signs (funduscopic examination and slit-lamp biomicroscopy)
    • Yellow-white deposits (drusen) between Bruch’s membrane and RPE
    • RPE pigmentary mottling: increased pigmentation
    • Geographic (RPE) atrophy: 
      • Seen in advanced dry AMD
      • Hypopigmentation or depigmentation of the RPE
      • Represents cell death in adjacent areas of RPE and photoreceptors 
  • Stages
    • Early stage: 
      • > 15 small drusen or < 20 medium-sized drusen
      • No vision loss
    • Intermediate stage:
      •  At least 1 large druse, ≥ 20 drusen or non-central geographic atrophy (fovea not involved)
      • May have vision loss
    • Advanced stage: 
      • Central geographic atrophy (fovea involved)
      • Noticeable vision loss

Wet AMD

  • Symptoms
    • Often bilateral, painless central visual distortion or loss
    • Acuity below reading and driving level
    • Can be gradual depending on pathology
    • Subretinal hemorrhage causes acute vision change.
    • Metamorphopsia: 1 of the earliest vision changes
    • Scotoma: partial alteration of vision in 1 spot but with normal surrounding visual field
  • Signs (funduscopic examination and slit-lamp biomicroscopy)
    • Neovascularization in the macula: gray-green discoloration 
    • Subretinal hemorrhage
    • Retinal pigment epithelial detachments (PEDs): separation of RPE from Bruch’s membrane
    • Subretinal lipid deposits on occasions
    • Disciform scars

Diagnosis

  • Clinical findings, dilated funduscopic examination with slit-lamp biomicroscopy
  • Amsler grid test: detects metamorphopsias and scotomas
  • Angiography
    • Fundus fluorescein angiography (FFA):
      • IV injection of fluorescein dye, which follows the course of choroid and retinal vessels
      • Hypofluorescence: hemorrhage
      • Hyperfluorescence: drusen, RPE atrophy, CNV membranes, serous PEDs 
    • Indocyanine green angiography
      • Uses a water-soluble tricarbocyanine dye
      • Detects choroidal neovascularization  and PEDs
  • Ocular coherence tomography (OCT)
    • Non-invasive imaging test utilizing light waves
    • Produces high-resolution cross-sectional retinal images
    • Detection of:
      • Drusen as nodular elevation of RPE
      • Retinal edema and subretinal fluid
    • Monitors treatment response in wet AMD
  • Color fundus photography: used to monitor AMD
  • Fundus autofluorescence
    • No contrast
    • Identifies lipofuscin accumulation (↑ in cellular aging)
    • Defines areas of geographic atrophy
Amsler Grid

1. Amsler grid: normal vision (left); 2. Amsler grid: AMD with metamorphopsia (right). Note the distorted lines.

Image: “Amsler Grid” by Africa Regional Medical Advisor: Fred Hollows Foundation, Kigali, Rwanda. License: CC BY 2.0

Management

Dry AMD

  • For all patients: smoking cessation
  • Monitoring of progression with regular follow-up
  • For intermediate AMD and advanced AMD: AREDS 2 (Age-Related Eye Disease Study 2) supplement daily
    • Vitamin C 500 mg
    • Vitamin E 400 international units (IU)
    • Zinc oxide 80 mg
    • Cupric oxide 2 mg
    • Lutein 10 mg
    • Zeaxanthin 2 mg

Wet AMD

  • AREDS 2
  • Intravitreal anti-VEGF 
    • First-line therapy; antiangiogenic
    • Ranibizumab: 
      • Recombinant humanized antibody fragment (Fab) that binds VEGF
      • 0.5 mg monthly for 3 months
    • Bevacizumab: 
      • Monoclonal antibody against VEGF
      • 1.25 mg monthly for 3 months
      • Lower cost than ranibizumab
    • Aflibercept: 
      • Recombinant fusion protein that acts as a VEGF receptor decoy
      • 2 mg every month for 3 months then every 2 months
    • Adverse effects: 
      • Endophthalmitis
      • Increased intraocular pressure 
      • Retinal detachment
      • Thrombotic events reported
    • Thermal laser photocoagulation
      • Rarely used due to recurrence of disease and poor visual outcomes
    • Photodynamic therapy
      • Application of light of specific wavelength and IV administration of verteporfin
      • Results in slowed CNV progression
      • Rarely used but an option in cases of failed anti-VEGF treatment
    • Surgery
      • Intravitreal tissue plasminogen activator with pneumatic displacement
      • Required in rare cases of submacular hemorrhage

Differential Diagnosis

  • Cataracts: a decrease in vision due to clouding of the lens, which presents as painless, blurry vision and glare problems. Cataracts are the leading cause of blindness worldwide. The condition can occur at any age, but most cases affect those > 60 years old.
  • Diabetic retinopathy: a visual impairment due to microvascular end-organ damage from diabetes mellitus. Diabetic retinopathy is classified as non-proliferative and proliferative retinopathy. Non-proliferative retinopathy is characterized by microaneurysms, intraretinal hemorrhages, exudates, and macular edema. The distinguishing feature of the proliferative type is the presence of retinal or optic disc neovascularization. Patients are initially asymptomatic but in the late stages present with decreased or fluctuating vision, possibly with floaters.
  • Retinal detachment: separation of the retina from the retinal pigment epithelium. This results in rapid photoreceptor damage. Symptoms include painless vision changes such as sudden flashes of light, floaters, worsening peripheral vision, or having a shadow in the field of vision. Retinal detachment is a medical emergency requiring corrective surgery.

References

  1. Ambati, J., Fowler, B. (2012 ) Mechanism of age-related Macular Degeneration. https://pubmed.ncbi.nlm.nih.gov/22794258/
  2. Arroyo, J., Gardiner, M., Schmader, K., Givens, J. (2020). Age-related macular degeneration: Treatment and prevention. UpToDate. Retrieved September 18, 2020, from https://www.uptodate.com/contents/age-related-macular-degeneration-treatment-and-prevention?search=macular%20degeneration&source=search_result&selectedTitle=1~66&usage_type=default&display_rank=1
  3. Arroyo, J., Gardiner, M., Schmader, K., Givens, J. (2020). Age-related macular degeneration: Clinical presentation, etiology, and diagnosis. UpToDate. Retrieved September 18, 2020, from https://www.uptodate.com/contents/age-related-macular-degeneration-clinical-presentation-etiology-and-diagnosis?search=macular%20degeneration&source=search_result&selectedTitle=2~66&usage_type=default&display_rank=2
  4. Handa, J., Rickman, C., Dick, A., Gorin, M., Miller, J., Toth, C.,Ueffing, M., Zarbin, M., Farrer, L. (2019). A systems biology approach towards understanding and treating non-neovascular age-related macular degeneration. Nature 10, 3347. https://doi.org/10.1038/s41467-019-11262-1
  5. Jonas, JB, Cheung, C., Panda-Jonas, S. (2017). Updates on the Epidemiology of Age-related Macular Degeneration. Asia Pacific J Ophthalmol 6 (6):493-497. doi: 10.22608/APO.2017251
  6. Maturi, R., Franklin, A. (2018). Nonexudative (Dry) Age-Related Macular Degeneration. Medscape. Retrieved September 19, 2020, from https://emedicine.medscape.com/article/1223154-overview
  7. Prall, F.R., Ciulla, T.,  Dahl, A. (2019). Exudative (Wet) Age-Related Macular Degeneration. Medscape. Retrieved September 19, 2020, from https://emedicine.medscape.com/article/1226030-overview

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