Age-related Macular Degeneration

Author: Ameen Marashi, MD

History

Documentation of age and visual loss is essential, which includes the photopsia, metamorphopsia, scotoma, and duration, along with detailed ocular history [1].

Medical history obtained to rule out drug hypersensitivity or history of hypertension and medication, nutritional diet, and nutritional supplements use [2]. As in diabetic patients with no coexisting diabetic retinopathy, metformin reduces the likelihood of developing ARMD [74].

Previous familial history of ARMD or other ocular or systemic diseases along with social history such as smoking [3], which accounts as a modifiable risk factor along with ethnicity, are documented.

Ocular Examination


A list of ocular examination should set

1) Best-corrected visual acuity (BCVA) for near and far is an essential step that can perform by a trained optometrist or certified ophthalmologist to document the visual impairment as poor BCVA at baseline is a poor prognostic factor for developing both non-geographic and geographic atrophy [60]. In general patients with baseline vision of 20/40 and more did better than patients with baseline vision of 20/40 and less [66].

2) A slit-lamp examination done with a thorough exam of clarity and regularity of the cornea and conjunctival abnormality such injection of conjunctival vessels should be documented, and any other inflammations of the conjunctiva or eyelids documented, along with iris exam and crystalline lens exam to rule out cataract or intraocular lens (IOL) to document the position and clarity of the posterior capsule.

3) Intra Ocular Pressure (IOP) documentation is essential as high IOP may be associated with a patient with glaucoma history.

Note when high IOP spotted a corrected IOP documented after central corneal thickness measurement.

4) Bilateral dilated fundus exam is an essential and detailed examination of the optic disc, macula, posterior pole, a mid-peripheral and peripheral retinal exam with specialized indirect wide-field lenses using slit-lamp biomicroscopy or indirect ophthalmoscopy to document the following:

1. A no or few small drusen (less than 63 μm) accounted for no ARMD.

2. A combination of small drusen and with few intermediate drusen (between 63 μm and 124 μm) or mild RPE changes categorized as early ARMD.

3. Intermediate ARMD features one of the following:

  • Numerous intermediate drusen

  • At least one large drusen (more than 125 μm)

  • Non-central geographic atrophy (well-demarcated area of RPE atrophy)

4. Advanced ARMD features the following:

  • Central geographic atrophy

  • Disciform scar (subretinal fibrosis)

  • Choroidal neovascular membrane (CNVm) maculopathy, which includes the following:

  1. Presence of CNVm.

  2. Subretinal or sub RPE fluids or hemorrhage.

  3. Retinal exudation with intraretinal cysts.

  4. Sub RPE vascular proliferation.

Patient education

It is essential to educate the patient about the importance of effective treatment, which depends on ocular findings and the need for regular follow up, especially in cases whenever there is visual worsening.

Amsler grid is a self-monitoring test which patients can perform at home as the patient should schedule for immediate retinal assessment by an ophthalmologist immediately in case of worsening [4].

Patients encouraged to use low visual aid devices, smartphones, or tablets to continue reading [5] and antioxidants supplements intake (if indicated) and to quit smoking.

Diagnostic tests

Fundus images

The Fundus image can help to document the severity and to follow up patients with ARMD as it helps in locating and measuring the size

of drusen along with geographic atrophy[6].

Hard drusen have distinct borders and smaller size while soft drusen larger in size with less distinct borders, when soft drusen enlarged in size (1/2 disc diameter) it defined as drusenoid RPE detachment [7], while geographic atrophy appears as patches of well-defined RPE atrophy, which may start non-

central or paracentral then progress to the center of the macula, drusen and drusenoid RPE detachments itself may turn in to geographic atrophy [8].

Fundus image documents the presence of intraretinal pigmentation, which is usually located anterior to the drusen and may overlay the RPE drusenoid detachment as a sign of chronicity. Still, when there is a cluster of pigmentations that it turns in to depigmented areas, it is a sign of developing geographic atrophy.

Usually, the larger the drusen or/and geographic atrophy, and the more central location and presence of pigmentation, the higher risk of developing CNVm.

Fundus Image very well documents the presence, size, and progression of subretinal scar in advanced stages of ARMD.

The choroidal neovascular membrane may have a gray-green reflex at the macula associated with subretinal hemorrhage or/not fluids with or without intraretinal exudation. At the same time, fibrovascular PED features irregular borders, while serous detachment has translucent content with smooth borders. In contrast, the hemorrhagic PED appears as deep red color, and when PED accompanied with active CNVm, it features subretinal fluids with or without hemorrhage and intraretinal exudation.

Polypoidal Choroidal Vasculopathy appears as Radish-orange rounded punched from the choroid into the subretinal area, and with or without subretinal fluids, blood, subretinal exudates and sometimes hard drusen.

Fundus imaging helps to follow-up the progression of ARMD +/- CNVm with or without treatment and document retinal finding changes [9].

Optical Coherence Tomography (OCT)

OCT is a useful tool to diagnose and follow up patients with ARMD which can help in determining treatment efficacy or progression of disease especially in cases of ARMD with CNVm where it shows the worsening or regression of subretinal CNVm, PED and changes in size and content of drusen and precise location and size of geographic atrophy and subretinal scar[10].

OCT has specific biomarkers that can help to identify the visual prognostic factors such as disturbance of external limiting membrane, or/and the ellipsoid zone or presence of intraretinal cysts, which hold bad visual prognosis [11] and may indicate the need for prompt treatment. In contrast, subretinal fluids may have a better visual prognosis. Still, it is a sign of active CNVm, especially in cases with

PED [12]. However, intraretinal cysts alone may not indicate active CNVm as it may be a sign of intraretinal cavitation; however, cases with active CNVm and intraretinal cysts are usually accompanied with increased retinal thickness or/and subretinal fluids [13].

Another feature of advanced ARMD that should be distinguished

from intraretinal cysts is outer retinal tubulation, which is located in the outer retinal tissues and distinguished as with hyperreflective borders with hyporeflective content with hyperreflective martial presenting enclosed photoreceptors and RPE cells [14].

OCT can accurately measure drusen sizes and distinguish it forms easily:

· Hard drusen looks like hyperreflective homogenous content without disturbing the ellipsoid zone; sometimes, it is associated with hyperreflective anterior to it resembling alternation of Henle’s layer and shouldn’t be mistaken with intraretinal pigment migration.

· Soft drusen appears larger size more homogenous and usually associated with a disturbance of ellipsoid zone

and hyperreflective foci anterior to it featuring intraretinal pigment migration.

· Regressing drusen may appear as heterogenous content accompanied with RPE atrophy and disturbed of both ellipsoid zone and outer retinal tissues.

· Drusnoid RPE detachment features larger size and homogenous content with ellipsoid zone disturbance and pigment migration.

· While reticular pseudo drusen, which are subretinal hyperreflective martial accumulation that can lay between ellipsoid zone and RPE, altering the contour ellipsoid zone or breaking the ellipsoid zone, which may hold prognostic factor of developing of advanced ARMD [15].

· Base laminal or cuticular drusen has the sawtooth shape with an increased signal transmission on the apex of the drusen in comparison to the edges of the drusen.

· Adult vitelliform dystrophy shows an accumulation of vitelliform material between the ellipsoid zone and RPE.

OCT in geographic atrophy appears as areas of attenuated RPE with only Bruch’s membrane visible and associated with the disturbance of ellipsoid zone and outer retinal tissue and increased reflectivity of the underneath choroid due to signal transmission and not reflected back by RPE. However, RPE can be incompletely atrophied, showing increased reflectivity of the choroid, disturbance, or attenuation of the RPE with degeneration of the photoreceptors layer.

Hyperreflective foci have an atrophic prognostic factor for RPE and photoreceptors, and the higher the number of hyperreflective foci, the higher the risk of atrophic changes [69].

OCT is a great tool to diagnose and categorized types of CNVm:

· Occult CNVm (type one) usually accompanied by fibrovascular PED, which contains heterogeneous content and with irregular borders but associated with visible Bruch’s membrane forming double-layer sign sometimes the PED contains hyper-reflective horizontal lines which indicate exudation from occult CNVm. Fibrovascular PED usually associated with subretinal fluids or hemorrhage, which are a sign of active CNVm, while cases of active occult CNVm associated with a disturbance of ellipsoid zone with or without intraretinal cysts which hold poor visual prognosis.

· In cases of treatment naïve quiescent CNVm, OCT shows irregular PED with the major axis in the horizontal plane, with moderate reflectivity with visible Bruch’s membrane without signs of exudation such as subretinal, intraretinal fluids, or increased retinal thickness. [40]

· Classical subretinal CNVm (Type two) features RPE defects with protruding subretinal amorphous mass, which contains fibrin, CNVm, and hemorrhage accompanied by subretinal fluids or/and hemorrhage with intraretinal cystic changes associated with a disturbance of ellipsoid zone.

· Retinal Angiomatous proliferation (CNVm type three) has three stages and is better diagnosed with ICG, which in OCT appears as intraretinal hyperreflectivity due to intraretinal capillary neovascularization with increased retinal thickness.

· Stage three appears as CNVm anastomosis with intraretinal neovascularization has unique findings OCT, which may feature PED with heterogeneous content with a break in the RPE connecting the content of RPE and hyperreflective martial just anterior to PED with increased retinal thickness with subretinal fluids or/and blood with intraretinal cysts.

· Sometimes CNVm type three associated with pre choroidal cleft as an area of hypo reflective space between Bruch’s membrane and PED content and holds bad visual prognosis and increased risk of developing RPE tear.

· Serous PED appears as an elevation of RPE with smooth or corrugated borders with clear fluid content. In contrast, the hemorrhagic PED, which contains blood and has increased reflectivity under the RPE, then hyporeflectivity due to signal blockage, both PEDs associated with disturbed ellipsoid zone or/and subretinal fluids (which may indicate the presence of active CNVm) and intraretinal cysts.

· RPE tear in OCT appears as indent of the retina with increased hyperreflectivity in the area of contracted RPE with underlying shadowing hinders choroidal view in contrast to the area where RPE was ripped off, Bruch's membrane is visible with increased visibility of the underlying choroid.

· Polypoidal Choroidal Vasculopathy appears as M-shaped or dome- shaped elevation of RPE, with visible choroidal polyps well adhered to RPE which may have clear fluid or hemorrhage beneath it, with prominent Bruch’s membrane (in case absence of blood) forming double layered sign along with subretinal fluid and less commonly intraretinal cysts formation and thus may explain better visual prognosis in some cases.

In cases of disciform scars, subretinal fibrosis appears as consolidated homogenous hyperreflective martial with RPE alteration but without an increase in the thickness of retinal tissue with disruption of the ellipsoid zone and outer retinal tubulation and sometimes it is combined

with intraretinal cysts which may not indicate an active CNVm and more as intraretinal degeneration. However, in cases of active CNVm, it may be accompanied by subretinal fluids or/and intraretinal cysts with increased retinal thickness. Choroid can be thinned in cases of advanced ARMD.

It is important to interpret the subretinal fluid with caution as it could be from exudative or transudative origin. The presence of subretinal SHRM or/and hemorrhage can indicate exudative origin. However, the transudative subretinal fluid can be due to a defect in the RPE pump, especially in cases presented with outer retinal tubulation and geographic atrophy. Therefore, it is imperative to rule out active macular neovascularization using OCTa or FFA.

Some cases presented with vitreomacular abnormalities such as an epiretinal membrane or/and vitreomacular traction, it will reduce treatment efficacy, and some cases may indicate surgical intervention to release the traction.

Optical Coherence Tomography angiography (OCTa)

OCTa is a non-invasive method (no need for intravenous dye injection) to detect and study the morphology and activity of neovascularization, which is very helpful in evaluating the impact of treatment on the CNVm itself.

CNVm may exhibit different shapes which indicate an activity or quiescent, as active CNVm may have three of the following features [16]

  • Well defined (lacy wheel or sea-fan shaped)

  • Branching with a dense network of the capillary.

  • Presence of anastomosis or loops.

  • Vessels have peripheral arcade form.

  • A halo perilesional.

In contrast, quiescent or regressed (post-treatment), CNVm has less than three of the features as mentioned above, which may appear like a dead tree.

When reading enface slabs of OCTa, CNVm type one may appear in the choroidal slab as a neovascular net while other slabs may not show any neovascularization. However, in type two, CNVm shows neovascularization more prominent in the outer retinal and RPE slab along with choroidal slab and can be surrounded with halo corresponding hemorrhage. However, in chronic type 2 CNVm, the neovascularization may appear not only in the outer retinal, RPE, and choroidal slabs, but it may also appear through all retina slab.

However, in cases of combined type 1&2 CNVm, type 2 appears through all retina slab and in outer retina/ RPE and choroid slabs while CNVm type one may appear only outer retina/ RPE and choroid slabs.

Macular neovascularization (MNV) type three (retinal angiomatous proliferation) shows intraretinal vascular complex emerges from deep capillary plexus and is usually correlated to adjacent telangiectatic vessels. MNV type three's persistence on OCTa may indicate the importance of continuous AntiVEGF treatment despite the lack of signs of exudation on OCT. Please note that the absence of MNV type three post-treatment doesn’t always mean that the lesion is completely regressed due to the reduced speed of blood flow on OCTa scans. However, the MNV type three lesion's recurrence on OCTa indicates the need for prompt treatment with intravitreal AntiVEGF [72].

In non-neovascular ARMD, in the area of geographic atrophy, the large choroidal vessels will be visualized due to loss of choriocapillaris and there would be a choriocapillaris flow deficit in the areas of geographic atrophy, and around it, drusen, and below hyperreflective foci [68]. However, the choriocapillaris flow deficit it can involve any areas in the scan region outside the geographic atrophy [71]. The choriocapillaris flow deficit on OCTa is an independent biomarker from changes on OCT for progression to geographic atrophy as each 1 % increase choriocapillaris flow deficit will have an 11% increase in the risk of progression to geographic atrophy [73].

Fluorescein Fundus Angiography (FFA)

FFA is an essential tool to establish the diagnosis of CNVm in cases of ARMD [17], especially in naïve/denovo cases where OCT or clinical examination can’t clearly diagnose it or in facilities where OCTa is not available.

In ARMD FFA may feature the following:

· Hard drusen may appear as well-demarcated hyperfluorescence in early phases without an increase in size in later phases.

· Soft drusen and drusenoid PED may appear as hyperfluorescence in mid phases and show staining in later phases; however, hyperpigmentation appears hypofluorescence in all phases.

· Geographic atrophy will appear as a well-demarcated area of hyperfluorescence, which won’t increase in size nor show any leak even it fades away in late phases and exhibits the characteristics of window defect.

· Subretinal scar (such as disciform) will appear as hyperfluorescence in mid phases and stains in late phases without showing any signs of leak or increase in size.

· Cuticular/Laminar drusen may appear as starry-sky appearance while reticular pseudodrusen may appear as fluorescence variation in the background in late phases


In cases of advanced ARMD associated with CNVm features the following:

· Fibrovascular PED shows early stippled hyperfluorescence source, which increases its intensity in mid and late phases and may or may not show leakage. Still, it shows dye pooling in late phases, which may be associated with subretinal dye pooling as a sign of subretinal fluids in active CNVm cases. One of the characteristics of active CNVm associated with fibrovascular PED is the presence of speckled hyperfluorescence in the mid and later phases.

· Another form of occult CNVm is leakage from an unknown source that may not have distinct borders as subretinal CNVm, but it shows leakage in late phases.

· In cases of treatment naïve quiescent CNVm, FFA will show ill-defined hyperfluorescence from CNVm without any leak in late phases. However, FFA plays a valuable role in active occult lesions that appear quiescent on SD-OCT, as FFA may show leakage [65].

· Subretinal CNVm, it clearly shows well-demarcated early hyperfluorescence of CNVm lesion even while choroidal filling then increases the intensity in mid phases and shows leakage in late phases, increasing in size with fuzzy, indistinct borders. Usually, subretinal CNVm is accompanied by subretinal dye pooling, which presents subretinal fluids, while intraretinal cystic formation may show hyperfluorescence in a pattern of cystoid macular edema.

· Serous PED may show hyperfluorescence in the area of PED with smooth borders. In later phases, it shows sub RPE dye pooling increasing in intensity without increasing in size with no leakage in late phases but may be associated with subretinal dye pooling as a sign of subretinal fluids; those cases may be associated with CNVm which will show adjacent leakage.

· Hemorrhagic PED show hypofluorescence due to blood blocks fluorescence but in those cases may be associated with CNVm which will show adjacent hyperfluorescence.

· Subretinal or intraretinal hemorrhages shows blocked fluorescence in all phases.

· Retinal angiomatous proliferation shows hyperfluorescence in the form of the intraretinal hotspot, which increases in size in late phases, which shows diving at a right angle toward the neovascular lesion and usually associated with small intraretinal hemorrhage.

· In cases of RPE tear, it shows a well-demarcated area of hyperfluorescence in all phases, which won’t leak but may show later staining of choroid and sclera adjacent to an area of hypofluorescence in area of contracted RPE and can be associated with leakage from adjacent CNVm.

· Polypoidal choroidal vasculopathy appears as hyperfluorescence may look similar to fibrovascular PED with hyperfluorescence notch resembling polyps surrounding subretinal dye pooling and may be accompanied with RPE atrophy inducing window defect. In the early phase, angiogram shows hyperfluorescence from Polypoidal choroidal vasculopathy, which is increased in mid-phase along with hyperfluorescence from PED, late phase angiogram shows leakage from polypoidal choroidal vasculopathy, sub RPE dye pooling, and subretinal dye pooling.

When classical CNVm occupies more than 50%, it is termed as predominantly classic while if occult CNVm occupies 50%, and more it termed as predominantly occult while if hemorrhage occupies 50%, it termed as predominantly hemorrhagic [18].

Note that the physician should obtain signed consent explaining the rare complications of FFA, including death 1/200000, and FFA facility should have an emergency plan in situ [19].


Fundus Autofluorescence (FAF)

This imaging technique is very helpful in evaluating the rate of enlargement and location of geographic atrophy as the areas of hypoautofluorescence indicate slow progression rate where areas of increased autofluorescence indicate rapid progression rates such as banded or diffuse pattern, as enlargement of geographic atrophy will follow to margins of increased autofluorescence [20].

Geographic atrophy appears as a well-demarcated area of hypoautofluorescence due to loss of lipofuscin while the junction area appears as increased autofluorescence which is classified as the following:

· Increased autofluorescence only at the margin of geographic atrophy which in term categorized as the following: Focal, Banded, and patchy, where focal has slow progression rate of geographic atrophy in contrast to banded which has rapid progression rate, however the patchy has no clear progression rate [20].

· Increased autofluorescence at the margin and elsewhere (diffuse) categorized as the following: fine granular, branching, trickling, reticular and fine granular with punctuated spots, which all have a rapid progression rate especially the diffuse trickling pattern [20].

Hard drusen may not show any increased autofluorescence. In contrast, soft drusen may show slightly increased autofluorescence, while drusenoid RPE detachment may show increased autofluorescence surrounded by a halo of decreased autofluorescence.

Indocyanine Green Angiography (ICG)

ICG becomes less utilized in diagnosing ARMD in the era of OCTa as CNVm will appear as a bright area of increased fluorescence (hot-spot), plaque, or ill-defined. However, ICG is best used to diagnose retinal angiomatous proliferation and polypoidal choroidal vasculopathy (PCV), which appears as hyperfluorescent polyps with branch vascular network (in polypoidal CNV cases) in early stages. In contrast, in later stages, the center of the polyp will appear hypofluorescent with hyperfluorescent surroundings.


B-scan

It is a useful technique to diagnose advanced ARMD with CNVm complicated with breakthrough vitreous hemorrhage and to rule out other causes of vitreous hemorrhage such as vascular or tumor. However, if the other eye retinal exam shows signs of ARMD, its suggestive vitreous hemorrhage caused by ARMD after ruling out other reasons such as vascular, PVD, or tumor.


Managing patients with ARMD


Treatment options


Oral supplements

AREDS proposed the original formula that contains high levels of Beta Carotene 15 mg, vitamin C 500 mg, and vitamin E 400 IU along with high levels of Zinc 80 mg reduce the risk of progression to intermediate or advanced when the fellow eye has advanced ARMD by 25% [21].

However AREDS 2 removed the Beta Carotene due to increased risk of developing lung cancer in smoking individuals along with competitive absorption to lutein/zeaxanthin, AREDS 2 replaced Beta Carotene with lutein/zeaxanthin [22] and the proposed daily

dose lutein/zeaxanthin 10mg/2mg with vitamin C 500 mg, vitamin E 400 IU and reduced Zinc dose to 25 mg and added Cupric oxide 2mg [23].

ARDES 2 didn’t show benefits for OMEGA 3 as an oral supplement [23], however rich OMEGA 3 intake in diet along with Mediterranean diet, including vegetables and fruits, may reduce the risk of development of advanced ARMD [24].

VEGF Blockade agents

Which are the most popular and proved both safety and efficacy and become the first line and mainstay therapy for cases of advanced ARMD with CNVm.

The commercially available VEGF blockade agents are Anti-VEGF such as Bevacizumab 1.25mg (0.05ml), which used off label

& Ranibizumab 0.5mg (0.05ml) and VEGF trap agents such as Aflibercept 2.0mg (0.05ml) and Conbercept (Available in China) [25].

New VEGF blockade agent approved by the FDA to treat advanced ARMD with CNVm is Brolucizumab 6.0mg, which has a high concentration and smaller molecular size when compared to other VEGF blockade agents which utilized as one injection every 12 weeks after three consecutive monthly injections (loading dose) [26].

However, Enríquez et al. reported in a multicenter retrospective case series that intraocular inflammation was 8.1% ranged from mild with a spontaneous resolution to severe despite the good efficacy for reduction of central macular thickness and visual stability [75] .

Due to the increased risk of intraocular inflammation, Brolucizumab can be used when switching to treat and extend after loading does with other agents or in recalcitrant cases to other VEGF blockade agents.


Injection technique

The injection should be carried out in sterile condition were injection site prepared by disinfecting the skin using povidone-iodine 10% After installing topical anesthesia, and the conjunctiva disinfected using povidone-iodine 4%.

The injection is carried out after placing sterile drape and lid speculum isolating eyelashes in the superior temporal quadrant.

Injection site measured with calipers 4 mm from the limbus

in phakic patients and 3.5 mm in pseudophakic or aphakic patients. A 30 gauge half-inch needle is used to inject VEGF blockade agents or steroids then a cotton tip applicator is placed over the injection site to prevent the reflux of fluid.

Photodynamic therapy (PDT)

It used to be the primary treatment before the Anti-VEGF. However, in the era of Anti-VEGF, PDT became less used and only utilized for cases of CNVm recalcitrant to Anti-VEGF or cases of PCV with or without Anti- VEGF, with an increased risk of RPE atrophy, choroidal ischemia, and visual loss.

The technique is by applying 6 mg/m2 of verteporfin with 10 minutes of infusion. After 15 minutes, an ICG guided photodynamic therapy applied using 689nm for 83 seconds delivering energy of 50 J/cm2 by the intensity of 600 mW/cm2 and spot size 1000 μm. To achive a half fluence PDT then use 25 J/cm2 of light at 300 mW/cm2

Laser Photocoagulation

Treatment of laser is widely abandoned by retinal physicians around the world due to complications such as visual threatening scar formation and maybe only utilized for non-central CNVm far enough that post- laser scar formation won’t cause visual loss or threatens the vascular avascular zone.


Surgical option

Pars plana vitrectomy indicated in situations of non-clearing vitreous hemorrhage or severe submacular hemorrhage, which is done

with subretinal injection of tPA using 41 gauge needle and pneumatic displacement and Anti-VEGF injection after removing the vitreous and inducing PVD.


Treatment Plan

Recommendations for early ARMD

No surgical or medical intervention warranted at this stage, as the development to large drusen is 15% within the next ten years. However, the patient should be encouraged to do self-monitoring using

the Amsler test, along with visiting their ophthalmologist for the retinal exam every 6 -24 months or whenever reduced vision reported.

No role for oral supplements of antioxidants, vitamins, or minerals, as oral intake supplements won’t reduce the progression of early ARMD to intermediate ARMD [27].


Recommendations for intermediate ARMD

Oral supplements, as described by AREDS 2 (See oral supplements in treatment options), are recommended in cases of intermediate ARMD in one eye, and advanced ARMD in the other or intermediate ARMD in both eyes as oral supplements can reduce the risk

of advanced ARMD development by 25% and reduce the risk of losing three lines by 19% in five years [28].

However, the patient should be encouraged to do self-monitoring using the Amsler test, along with visiting their ophthalmologist for a retinal exam every 6 -18 months or whenever reduced vision is reported.

Recommendations for non-neovascular advanced ARMD

In non-smoker individuals, oral supplements, as described by AREDS (See oral supplements in treatment options), are indicated when one eye is suffering from advanced ARMD and the other eye has large drusen or RPE abnormalities.

In non-smoker individuals, oral supplements, as described by AREDS, are indicated when there is advanced ARMD in both eyes with at least one of the eyes has CNVm, and at least one of the eyes has vision 20/100 and better to decrease visual loss in non-neovascular advanced ARMD.

In smoker individuals, it is recommended to use the AREDS 2 formula and to advise the patient to cease smoking.

However, the patient should be encouraged to do self-monitoring using the Amsler test, along with visiting their ophthalmologist for a retinal exam every 6 -18 months or whenever reduced vision is reported.

Recommendations for advanced neovascular ARMD


In cases of treatment, naïve quiescent CNVm

No treatment required only observation and repeat OCT and OCTa or FFA every six months, and even if CNVm grows in size.

Treatment initiated only when there is exudation in the form of subretinal, with or without intraretinal fluids with increased retinal thickness with one injection of Anti-VEGF then monthly OCT [41].

“Patients with serous and hemorrhagic PED with no signs of active CNVm do not warrant treatment with Anti-VEGF as regressing PED alone won’t improve vision”

In cases of active CNVm not threatening the fovea

- Only observation is warranted but with lower duration intervals recommended every two weeks then monthly then bi-monthly then every four months and then every six months, if it didn’t progress to the center or reduced vision documented during follow-ups; however, if the CNVm progressed or started to threaten the center of the fovea and can cause reduced vision intravitreal injection of Ant- VEGF warranted to regress the CNVm (see the below recommendations)

- The laser can be utilized, but only for CNVm far enough that post-laser scar formation won’t cause visual loss or threaten the vascular avascular zone.

- In the case of non-central active CNVm progressed to central causing visual loss, the case should be managed as active CNVm involving the fovea.


In cases of active CNVm threatening or involving the fovea

- In these cases, the monthly intravitreal injection of Anti-VEGF recommended promptly for three consecutive monthly injections as a loading dose [29].

- This applies to all subtypes of CNVm and PED (except for drusenoid PED), where all VEGF blockade agents may have a similar effect[30],Aflibercept may be more effective in cases presented with PED [31], however, when comparing Ranibizumab with Bevacizumab, Ranibizumab is slightly more effective (especially in when used as needed), though Bevacizumab is more cost-effective [45]

-Regression of CNVm evaluated four weeks after the third injection based on OCT or/and OCTa, where OCT shows resolution

of subretinal, intraretinal fluids, or sub RPE thickening (PED). [12] OCTa may show the dead tree pattern (please see the OCTa section), where FFA shows no leakage.

- Clinical examination alone is not enough to judge the regression of CNVm. At the same time, vision may improve after the first injection and then the stability of vision in the next two injections.

- When CNVm regresses after the loading dose, treating physicians can continue with the patient with monthly injections, T&E, or PRN (please see the follow-up section, where protocols are explained in detail).

-If Brolucizumab is used as the loading dose, then reinjection is warranted every 12 weeks after the three-monthly consecutive injections [26].

-If the other eye has large drusen with or without RPE abnormalities or non-neovascular advanced ARMD with vision 20/100 and better, then oral supplement indicated as recommended by AREDS (please see the recommendations for non-neovascular advanced ARMD).

In cases of stable active CNVm threatening or involving the fovea after the loading dose

-If CNVm becomes less active after the loading dose based on OCT as residual subretinal, intraretinal fluids and thickening, or residual leakage on FFA.

- If CNVm stable or showed improvement but not regressed based on OCT, OCTa, or FFA, then a continue with additional three injections of Anti-VEGF recommended.

- If the other eye has large drusen with or without RPE abnormalities or non-neovascular advanced ARMD with vision 20/100 and better, then oral supplement indicated as recommended by AREDS (please see the recommendations for non-neovascular advanced ARMD).

In cases of persisting or worsening of active CNVm threatening or involving the fovea after the loading dose

- If CNVm remained active or became worse after the loading dose based on OCT as presentient subretinal, intraretinal fluids and thickening, active CNVm features on OCTa, or presentient leakage on FFA along with reduced vision and persisted hemorrhage on clinical examination.

- If CNVm showed no response or worsening based on OCT, OCTa or FFA, then switching Anti-VEGF recommended, for example, if the used agent was Bevacizumab, then switching to Aflibercept may help [32].

However, if CNVm kept on persisting or worsening even after switching VEGF blockade agents, then PDT recommended in these cases [29].

-If the other eye has large drusen with or without RPE abnormalities or

non-neovascular advanced ARMD with vision 20/100 and better, then oral supplement indicated as recommended by AREDS (please see the recommendations for non-neovascular advanced ARMD).

In cases of submacular hemorrhage

-OCT and fundus imaging can help to show the location, size, thickness, and etiology where ICG can be used in case OCT or OCTa failed to reveal the source of hemorrhage [33].

- Anti-VEGF recommended in eyes with good vision, and short duration of hemorrhage, which may provide visual improvement with careful monitoring and regular follow up [34].

- Intravitreal tPA with pneumatic displacement and intravitreal Anti- VEGF recommended for patients with a medium to large hemorrhage or

thick submacular hemorrhage and presented with poor vision at baseline (less than 20/200) [35].

- In cases of severe submacular hemorrhage with poor visual acuity at baseline, pars plana vitrectomy with subretinal tPA, pneumatic displacement, and Anti-VEGF is a better option than Anti-VEGF alone as a solo therapy. Therefore, surgical intervention recommended in severe submacular hemorrhage as presented by thickness and location [36].


In cases of RPE tear

Despite that, Anti-VEGF may be a contributing factor for inducing RPE tear that does not contraindicate further injections. Indeed, continuous injection with Anti-VEGF needed to regress active CNVm to reduce further visual loss from CNVm exudation [42]; however, in cases with inactive CNVm only observation warranted.


In cases of polypoidal choroidal vasculopathy (PCV)

-In cases of PCV, three monthly consecutive intravitreal

Anti-VEGF injections recommended then re-evaluate using OCT [37].

-In cases that PCV failed to respond

to Bevacizumab or Ranibizumab, then Aflibercept recommended as it is more effective than Ranibizumab and Bevacizumab [38].

-However in cases that PCV failed to respond to monotherapy then it should be combined with half-dose PDT [39], especially six months after failure with intravitreal Anti-VEGF monotherapy.[76]

ARMD and Cataract surgery

Cataract surgery is not contraindicated in light of ARMD, even in cases of active neovascular advanced ARMD, as cataract surgery itself won’t exacerbate ARMD in all its forms. Indeed, cataract removal may enhance visual function and provide clear media for optimum follow- up [43]. It is advisable to implant monofocal intraocular lenses for ARMD patients scheduled for cataract surgery.

ARMD and Aspirin

The physician should encourage patients NOT to stop aspirin as there is no risk of increased subretinal hemorrhage; however, warfarin may contribute to subretinal hemorrhage [44].


Flow chart summarizes the approach and management of age-relatd macular degeneration

Follow up and prognosis

-In patients with early ARMD has very low risk in developing advanced ARMD, where in cases of intermediate ARMD with large multiple drusen, the risk of developing advanced ARMD within five years 6.3% if one eye involved and 26% if both eyes involved [46]. However, in patients with intermediate ARMD but medium-sized drusen, the risk for progression to advanced ARMD is 14% within ten years, and the risk to develop large drusen is 37% if one eye involved and 71% if both eyes are involved [47].

-In cases of intermediate ARMD, visual loss occurs by 21% for more than three lines within five years [48] or by 20% for more than six lines within two years [52].

-In patients with drusenoid PED, the risk of development of Advanced ARMD 42% within five years [49].

-In patients with large bilateral drusen, the risk of development of neovascular ARMD is 32%, and when presented with RPE abnormalities, it is 45% within ten years [47].

-When one eye suffering from advanced ARMD, the other eye may progress to advanced ARMD between 35% to 50% within five years [50] this depends on the status of the healthy eye, for example, the severity of geographic atrophy, the severity of pigmentation, quantity, and size of drusen [51].

-In patients with advanced ARMD, 16% of eyes progressed to neovascular ARMD if the fellow eye didn’t have neovascular ARMD and 36% if the fellow eye had neovascular ARMD [53].

-In cases of neovascular ARMD, patients are followed up for at least two years. Treatment withheld after regression of CNVm and absence of signs of exudation on OCT such as subretinal and intraretinal fluids with reduced sub RPE thickening there are several treatments follow up protocols:

1. when CNVm regressed, the patient followed up monthly evaluating for worsening in visual acuity and signs of CNVm reactivation using OCT such as subretinal fluids and increased central macular thickness and signs of active CNVm on OCT or renewed leak on FFA; if any, then monthly injection until CNVm regressed again, then a monthly follow up is recommended [54].Non-central stable subretinal fluids not associated with subretinal hemorrhage or fibrin can be tolerated.

2. Treat and Extend (T&E): when CNVm regression achieved four weeks after the loading dose, the patient receives additional intravitreal injection after two weeks and re-evaluated after eight weeks. If there is no sign of CNVm activation, a further injection added, then patient evaluation and treatment extended for more two weeks, but the extension shouldn't exceed 12 weeks. During the T&E follow up if a sign of reactivation of CNVm (as mentioned above) is noticed, then a switch to monthly injection until CNVm regresses again then follow up extended again [55].

3. injection continued for monthly injection for two years despite the inactive CNVm, although this technique may offer better visual outcomes than the other forms, but it is not cost-effective and required high patient compliance [56].

- Clinical trials showed the superiority of T&E over PRN in terms of visual acuity, but T&E requires more injections; however, it is worth noting that visual loss will be more than in monthly protocol [57].

-Patients with neovascular ARMD may have improved vision in the first two years of treatment with Anti-VEGF. However, vision may deteriorate within the next 8.7 years. Thus, patients with initial good visual acuity at the baseline and those treated earlier have a better visual prognosis [67].

-Treatment of AntiVEGF was related to preserved beneficial vision in 20 % of patients (12 % of patients can drive, and 15 % can read) in a remaining average lifetime. Still, vision can deteriorate If treatment with Anti-VEGF is stopped. In contrast, 80% of patients can end up with legal blindness within three years in cases without intervention [70].

-One of the reasons for visual loss post successful intravitreal Anti- VEGF treatment is scar formation [58].

-Patients with serous and hemorrhagic PED have poor visual prognosis despite successful treatment [59].

- When treating patients with neovascular ARMD, non-geographic atrophy may occur in about half of the patients within two years, and geographic atrophy may occur after further three years in half of the patients [60].

- Patients with neovascular ARMD are at high risk of developing Macular atrophic changes in cases of nascent atrophy, reticular pseudo drusen, thinning of the choroid, increased foveal thickening, and high central drusen volume is new OCT risk factors for macular atrophy development [61]. Along with the presence of intraretinal fluids, geographic atrophy in the other eye, and CNVm type three. However, intravitreal Ranibizumab monthly or every 12 weeks didn’t increase the risk of macular atrophy [62]. But within two years of treatment with VEGF-blockade agents, eyes with more retinal thickness fluctuation had worse best-corrected visual acuity. They had more chance to develop fibrosis and geographic atrophy in the macula than eyes with less fluctuation [63]. In cases of polypoidal choroidal vasculopathy are at risk of developing macular atrophy in 10 % of cases [64].



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These guidelines were reviewed and updated in June 2021