Acquired Maculopathy and Other Posterior Disorders

Acquired Maculopathy and Other Posterior Disorders

Joseph Sowka, OD, FAAO, Diplomate

Age-Related Macular Degeneration (AMD): The Continuum of Normal Aging and Disease

·  Degenerative Changes

·  RPE and Bruch’s membrane disturbances

·  Formation of drusen

·  These changes are commonly observed in the eyes of most elderly persons to some degree

·  Cell death and functional loss

·  Only in some individuals do these age related changes progress to this stage

·  Transition from normal aging to disease (with a loss of functional vision)

·  Drusen are players in retinal disease, RPE disease, and AMD

·  Drusen occurs in 70% of all eyes over the age of 50 yrs

·  Drusen are signs of RPE abnormality/ atrophy

·  Precursor/ participant in AMD

·  Peripheral/ posterior pole location

·  RPE cells deposit collagenous basement membrane into Bruch's (drusen):

·  Mucopolysaccharides and lipids.

·  Cause unknown (choriocapillaris dysfunction?)

·  Solar exposure

·  Photodynamic effects can lead to superoxide free radical formation, which promotes drusen/ lipofuscin formation. Lipofuscin and drusen are thought to be RPE phagocytized photoreceptor outer segments that are driven by a solar induced mechanism.

·  Increased deposition of drusen is associated with RPE thinning and atrophy

·  Choriocapillaris breakdown results in hypoxia (and release of VEGF), RPE atrophy, and drusen formation

·  Pathophysiology and implications of drusen are not fully understood- Drusen do alter Bruch's membrane and can lead to choroidal neovascularization

·  Hard drusen

·  Typically seen in dry AMD

·  Soft drusen

·  Amorphous material between inner and outer layers of Bruch's membrane

·  Large, ill-defined, confluent

·  More inclined to lead to exudative (wet) AMD

·  Allows formation of choroidal neovascular membrane (CNVM)

·  As RPE atrophy increases, the risk of wet AMD decreases. RPE atrophy represents poor choroidal perfusion and hypoxia- neo can not be supported due to choriocapillaris dropout. However, vision still suffers.

Age Related Macular Degeneration (AMD): Risk Factors

·  Typical age: 75-85 years

·  Framingham population-based prevalence study criteria: 20/30 or worse

Prevalence:

52-64 yrs / 1.6%
65-74 yrs / 11%
75 yrs + / 27.9%

·  Family hx

·  Maternal or sibling history strongest

·  Hand grip weakness

·  Alcohol consumption

·  Cardiovascular disease

·  Hypertension

·  Hyperlipidemia

·  Hyperopia

·  Aphakia

·  Short stature

·  Lightly pigmented hair/ eyes

·  Caucasian

·  Wet form more common in Caucasian patients

·  Smoking (esp. men)

·  Heavy smoking more than doubles risk

·  Nutritional

·  Decreased vit B,E zinc, magnesium intake

·  Higher incidence with alcohol consumption: poor diet

·  However, moderate intake of wine and carotenoids (leafy greens) may help

·  Leutein may be most protective

·  Drusen (as discussed above)

·  Wet: soft drusen

·  Dry: hard drusen

Dry (Atrophic or Non-exudative) AMD

·  80% of AMD cases

·  Macular drusen is a risk factor for both wet and dry AMD

·  Soft drusen – typically wet AMD

·  Hard drusen – typically dry AMD

·  Depigmentation

·  Granular clumping of RPE/RPE hyperplasia

·  Macular RPE atrophy

·  Mottled, "moth eaten" appearance of retina/RPE

·  Coalesce into geographic atrophic areas of RPE and choroid

·  200-5000 microns (1/7DD-3DD)

·  Bilateral, symmetrical

·  10% will progress to wet AMD

Clinical Pearl: Dry AMD is not diagnosed by a single finding, but instead constitutes a spectrum of findings involving drusen, RPE atrophy, functional vision loss and/or RPE pigment changes. The beginning of the spectrum constitutes normal aging changes and the end represents severe vision loss.

Dry AMD: Geographic Atrophy

·  Progressive loss of RPE and choriocapillaris

·  Macrophages replace drusen with fibrous tissue or dystrophic calcification

·  Once this occurs, CNVM will no longer form

·  Loss of photoreceptor function

·  Non-viable capillaries: neo will not form in non-viable, atrophic zones

·  20% risk of CNVM at edge of lesion

·  Loss of retinal layers

·  VA 20/25 - 20/400 (approx)

Dry AMD: Management

·  Photodocument

·  Home amsler

·  UV protection

·  Anti-oxidant vitamins with zinc supplements (Results of the Age-Related Eye Disease Study (AREDS): Archives of Ophthalmology October 2001, JAMA October 2001)

·  For those taking high-potency antioxidants and zinc combined formula, there was a decrease (vs placebo) in the percent of patients who progressed to advanced AMD at 5 years

·  Visual acuity loss

·  Only the high-potency antioxidants (vitamin C, vitamin E, beta carotene) and zinc combined formula statistically significantly reduced the odds of visual acuity loss

·  Neovascularization

·  The combined high-potency antioxidants and zinc product statistically significantly reduced the odds of developing choroidal neovascularization

·  Conclusions: Those with extensive intermediate sized drusen, at least one large drusen, or non-central geographic atrophy in one or both eyes or those with advanced AMD or vision loss due to AMD in one eye and without contraindications such as smoking, should consider taking a supplement of antioxidants plus zinc

·  F/u q3mos-q6mos

·  Low vision consult

·  90% of dry AMD pts are not legally blind

Wet (Exudative) AMD: Choroidal Neovascularization

·  8-20% of cases of AMD are wet (actually, up to 12% may be unknown, according to Framingham study)

·  Presence of exudate, hemorrhages, or suspected gray-green lesion as this implies that choroidal neovascularization and wet AMD has formed. However, hemorrhage or exudation may obscure part or all of CNVM

·  Choroidal Neovascularization

·  Bruch's disruption

·  Diffuse thickening of Bruch’s with soft drusen which predisposes to breaks in Bruch’s membrane

·  Presence of VEGF enhances development

·  Other diseases can cause Bruch’s disruption

·  RPE/ Bruch's breaks

·  Diffuse thickening with soft drusen predisposes Bruch’s membrane to breaks

·  Soft drusen often precursor, but not always

·  Chronic Inflammation Theory

·  Higher number of lymphocytes, macrophages, fibroblasts found in Bruch’s membranes of patients with AMD

·  Inflammation causes breaks in Bruch’s membrane?

·  Implication are not yet understood

·  Choroidal neovascular membrane (CNVM) infiltrates from choriocapillaris

·  Under the RPE and sensory retina

·  RPE detachment with turbid fluid or blood may represent CNVM

·  Round/oval gray-green elevation

·  Don’t look only for gray-green appearance. Look for fluid and blood.

·  Associated findings:

·  Lipid exudate

·  Blood

·  Sensory RD

·  Classic CNVM

·  Well defined membrane on angiogram

·  About 10% of cases

·  Occult CNVM

·  About 90% of cases

·  Ill defined membrane on angiogram

·  CNVM may be subfoveal, juxtafoveal (1-199 microns from center of macula), or extrafoveal (> 200 microns from center of macula

·  FA and possibly indocyanine green (ICG) imaging: hot spots with late spread of hyperfluorescence.

·  Must get FA within 72 hrs because membranes can grow 10 microns/day; Suspected/actual CNVM is an ocular urgency

·  ICG may be indicated to better visualize outline of membrane

·  ICG dye absorbs and emits fluorescence in the near IR spectrum

·  Better able to penetrate hemorrhage, melanin, fluid

·  Better for occult CNVM detection

·  Hypoxia and VEGF

·  RPE tear

·  Serous RPE detachments

·  Hemorrhagic RPE/sensory retinal detachments

·  10% risk of wet AMD in 4.3 yrs if pt. has bilateral macular drusen

·  90% of pts. who are legally blind from AMD have wet AMD

·  VA 20/200-20/800

Clinical Pearl: Sub-retinal hemorrhages are identified by your ability to see distinct retinal vessels overlying the hemorrhaging area. If you can see the retinal vessels, then the hemorrhage must be beneath the retina.

Clinical Pearl: Soft drusen are more inclined to lead to wet AMD

Wet (Exudative) AMD: Disciform Scarring:

·  Fibrovascular material following CNVM development

·  Most cases of CNVM progress to this stage

·  Replaces most of sensory retina, RPE

·  May continue to grow and invade new areas

·  Results in death of tissue and severe visual loss

·  Yellow-brown-black (RPE hyperplasia)

·  Surgical excision may modestly improve vision

Wet AMD: Management

·  Laser photocoagulation

·  Photodynamic therapy (PDT)

·  Intravitreal steroid injection

·  Anti-angiogenic factors

·  UV protection

·  Anti-oxidant vitamin therapy

·  Macular drusen - home amsler

·  Low vision consult

Wet AMD: Laser Treatment

·  50% of wet AMD cases are potentially laser treatable with subsequent reduction in vision loss (i.e., the CNVM is juxta-or extrafoveal)

·  Of those pts. (the 50%) that are treatable:

·  75% of wet AMD pts pass through this "treatable" stage

·  80% are treatable within 2 weeks

·  Only 50% are treatable in 4 weeks

·  Only 20% are treatable in 8 weeks

·  Krypton laser for juxtafoveal net (less likely to be absorbed by RPE)

·  Specificity for choroidal layers

·  Recurrence rate: 47% of tx’ed eyes

·  Argon Study: argon laser for extrafoveal net (>200 microns from center of FAZ)

·  Treat with argon blue-green laser

·  Laser energy absorbed by RPE and choroidal pigment and turned into heat and dissipated into adjacent tissues. CNVM are closed by coagulative necrosis

·  Xanthophyll pigment absorbs green argon laser and transmits heat to adjacent structures, thus cannot be used juxtafoveally.

·  Recurrence rate after treatment- 53%

·  There is no good treatment for a subretinal/ subfoveal hemorrhage. Some surgeons will inject a gas bubble into the eye and place the patient face down in order to tamponade the hemorrhage and spread the blood out.

·  There is no great treatment for a subfoveal CNVM. Some surgeons are lasering subfoveal membranes in the thought that the laser damage will be less severe than the natural course of the disease.

·  Short-term results are significantly reduced vision. However, long-term results support treating sub-foveal CNVM as these patients do better. However, patients can often retain good vision with a subfoveal CNVM for an indeterminate period of time. Laser reduces vision immediately. This treatment should only be done after vision has dropped to 20/200

Wet AMD: Photodynamic Therapy (PDT)

·  Patient receives IV infusion of a light activated drug that collects in the tissues of the macula. Low powered laser (664 nm) activates the drug, which forms singlet oxygen. This induces platelet aggregation and thus CNVM thrombosis. This is chemical obliteration of CNVM without damaging overlying retina and RPE. Damages unhealthy tissue but does not disturb healthy adjacent or overlying tissues.

·  Difficulty: Indicated only for subfoveal membrane whose areas is at least 50% ‘classic’ CNVM. Only about 10% of CNVM are ‘classic’.

·  Another problem: PDT causes up-regulation of VEGF which increases leakage and propensity to form neovascularization

·  Verteporfin: Visudyne

·  High rate of side effects

·  Highly photosensitizing. Must absolutely avoid the sun for 3 days

·  High degree of skin necrosis needing skin grafts if dye extravasates during injection

·  Can not have subretinal fibrosis

·  Leakage is reduced, but not stopped

·  70-80% leak again in 1 year; however, doesn’t bleed, scar, or atrophy

Clinical Pearl: Photodynamic therapy is a well-accepted therapy for wet AMD, though the stand-alone results are not great. Likely, it will be used in conjunction with other therapies for best results.

Wet AMD: Intravitreal Steroid Injection:

·  Stabilizes vascular membranes and reduces vascular permeability.

·  Endophthalmitis is most significant complication

Clinical Pearl: Intravitreal injections of steroids are being investigated and used for edema secondary to vascular occlusions, diabetes, cystoid macular lesions, and wet age related macular degeneration. This promises to be a significant advancement in the treatment of maculopathies secondary to edema.

Wet AMD: Anti-angiogenic Therapy

Macugen (pegaptanib sodium)

·  Oligonucleotide with high affinity for VEGF, preventing its uptake by endothelial receptors

·  Intravitreal injection q 6 weeks

·  Approved, but has not fared well and is not commonly used as other chemicals have performed better

·  Stand-alone therapy

·  87.5% of eyes had stabilized or improved vision after 3 months

·  25% of eyes improved three or more lines

·  Macugen + PDT

·  60% of eyes improved three or more lines at 3 months

Lucentis (ranibizumab)

·  Recombinant anti-VEGF antibody fragment that binds to VEGF

·  Intravitreal injection q 4 weeks

·  Approved and more successful than Macugen

·  94% of eyes with stable or improved vision at 98 days

·  On average, two lines of vision gained

·  26% of eyes improved three or more lines at 98 days

·  Studies comparing monthly Lucentis injections vs. quarterly PDT are being done

Avastin

·  Anti-colon cancer drug; accidentally found when patients with wet AMD patients undergoing chemotherapy reported improved vision

·  Not approved for this use (intravitreal injection for AMD), but very popular and economical

Clinical Pearl; Despite all of the new developments in wet AMD management, if a patient develops subfoveal CNVM today, he or she is pretty unlucky.

Other Conditions Associated with Choroidal Neovascular Membrane Formation:

·  Degenerative conditions

·  Wet AMD (#1 cause)

·  Degenerative myopia (#3 cause)

·  Angioid streaks

·  ONH drusen

·  Idiopathic Central Serous Chorioretinopathy (ICSC) and RPE detachment

·  Inflammatory and infectious conditions

·  Ocular Histoplasmosis syndrome (#4 cause)

·  Toxoplasmosis

·  Tuberculosis

·  Sarcoidosis

·  Syphilis

·  Rubella

·  Choroidopathies (serpiginous, birdshot, punctate inner)

·  Beçhet’s syndrome

·  Vogt-Koyanagi-Harada syndrome (VKH)

·  Hereditary

·  Best’s disease

·  Dominant drusen

·  Fundus flavimaculatis

·  Choroideremia

·  Retinitis pigmentosa (RP)

·  Tumors

·  Malignant melanoma

·  Choroidal hemangioma

·  Metastatic tumors

·  Trauma

·  Excessive PRP

·  Choroidal rupture

·  Miscellaneous

·  Idiopathic CNVM (#2 cause)

·  Radiation retinopathy

·  Retinal detachment

·  Tilted disc syndrome

Choroidal Rupture

·  Result of direct injury to globe

·  Hemorrhages present if recent