Cystoid Macular Edema (CME)

Cystoid Macular Edema (CME)

• Retinal thickening occurs in the macula due to a disruption of the normal blood-retinal barrier.
• Leakage from perifoveal retinal capillaries leads to fluid accumulation within intracellular spaces of the retina.
• Primarily affects the outer plexiform layer (Henle’s layer) and the inner nuclear layer, but can also affect the subretinal space.
• Muller cell dysfunction contributes to intracellular swelling, exacerbating retinal interstitial disruption and promoting edema and neurodegeneration.
• CME is a finding, not a diagnosis, resulting from various causes.
• Named for its polycystic petaloid appearance on fluorescein angiography.
• Mediators that disrupt the blood-aqueous barrier (and blood-retinal barrier) increase vascular permeability.
• Prostaglandins contribute to tissue inflammation, vasodilation, and vasopermeability.

CME Etiology

• Drug-induced causes include topical prostaglandins, topical adrenaline derivatives (especially in aphakic patients), and nicotinic acid.
• Retinal dystrophies (RP).
• Diabetic retinopathy (DR) which is the second most common cause.
• Vascular occlusive disease.
• Pars planitis.
• Posterior uveitis.
• Epiretinal membrane (ERM), vitreomacular traction (VMT), or posterior vitreous detachment (PVD).
• Macular telangiectasia (Mac Tel).
• Choroidal neovascularization (CNV).
• Fundus tumors.

Systemic Diseases Associated with CME

• Systemic hypertension (HTN).
• Collagen vascular diseases.
• Multiple myeloma.
• Leukemia.
• Chronic renal failure.

Trauma-related CME

• Post-surgery, especially Nd:YAG laser capsulotomy, panretinal photocoagulation (PRP), retinal detachment surgery, and glaucoma surgery.
• Pseudophakic cystoid macular edema (PCME) is most common after cataract surgery.
• Higher incidence with extracapsular cataract extraction (ECCE).
• PCME is also known as Irvin-Gass Syndrome.

Pseudophakic Cystoid Macular Edema (PCME)

• Incidence is around 20-30%, but many patients post-phacoemulsification show mild PCME on angiography.
• Improved surgical techniques and drug therapy have reduced PCME incidence to 0.1%-3.8%.
• Most patients with PCME detected only with tests are asymptomatic and need no intervention.
• Peak incidence occurs at 6-10 weeks post-surgery, but onset can be much longer.

Risk Factors for PCME

• Diabetes and uveitis.
• Epiretinal membrane.
• Primary open-angle glaucoma (POAG).
• History of CME in the other eye.
• Operative complications like posterior capsular rupture with vitreous loss, especially with vitreous incarceration into the incision site.
• Anterior chamber intraocular lens (IOL) or secondary IOL implantation.
• Topical prostaglandin treatment.
• Most symptomatic Irvin-Gass Syndrome cases resolve spontaneously within 8 months; 50% resolve sooner.
• Rarely, PCME can remain angiographically or OCT detectable for over 5 years.

PCME Pathogenesis

• Inflammatory mediators released into the anterior chamber during cataract surgery diffuse to the posterior segment of the eye causing vasodilation.
• Vascular permeability increases, disrupting the blood-aqueous and blood-retinal barrier (BRB).
• Prostaglandins and vascular endothelial growth factors (VEGFs) are examples of inflammatory mediators.
• CME develops when transudate accumulates in the outer plexiform layer (OPL) and inner nuclear layers of the retina.

PCME Symptoms

• Decreased vision due to fluid accumulation.
• Blurry vision.
• Distorted vision: metamorphopsia.
• Decreased photostress test results.

PCME Signs

• Loss of foveal depression.
• Thickening of the retina with or without small intraretinal cysts in the foveal region.
• Irregularity and blunting of the foveal light reflex.
• Multiple cystoid areas.
• With a red-free filter, CME appears as a light gray, fluid-filled area in the macula.
• On fluorescein angiography (FA), a petaloid pattern is observed.
  • Early stages: hyperfluorescent spots.
  • Late stage: late petaloid pattern with microcystic spaces in the OPL, specifically in Henle’s layer.

PCME Treatment

• Topical NSAIDs are usually the first-line treatment, alone or combined with topical corticosteroids.
  • Examples include Ketorolac 0.5% QID, Bromfenac 0.09%, or Nepafenac 0.3% daily, often with Prednisolone acetate 1% QID.
• Common dosing ranges from QID to every 2 hours; a loading dose of every 2 hours may be initiated and then quickly reduced to QID after a few days.
• Treatment duration can range from several days to months, depending on CME severity.
• Ex: Acular QID and Pred Forte QID.
• For high-risk patients, consider NSAIDs a week before surgery.
• Some patients do not respond well to therapy and experience chronic or recurrent edema.
• Injectable treatments, including intravitreal anti-VEGFs, steroids, sub-Tenon steroid injections, and intravitreal steroid implants, are used off-label in these cases.

PCME Other Treatments

• Systemic steroids (e.g., Prednisone 40 mg PO daily for 5 days, then taper over 2 weeks).
• Systemic NSAIDs (e.g., Indomethacin 25 mg PO TID for 6 weeks).
• Topical or systemic carbonic anhydrase inhibitors (CAIs) like Dorzolamide 2% TID or Acetazolamide 500 mg PO daily (also used in RP-associated CME).
• Vitrectomy or YAG laser lysis of vitreous strand may improve CME with or without vitreous incarceration in a surgical wound.

PCME Follow-Up

• Follow-up in 4 weeks.
• Postsurgical CME patients should start on a topical NSAID and a topical steroid, with follow-up in 4-6 weeks to assess response.

Central Serous Chorioretinopathy (CSCR)

• Pachychoroid disease phenotype.
• Pachy = thick (>390 μm; normal is 250-350 μm).
• Attenuation of the choriocapillaries over dilated choroidal vessels.
• Associated with progressive RPE dysfunction and neovascularization.
• Characterized by dilated choroidal vessels in Haller's layer, with thinning of the choriocapillaris and Sattler layer (pachyvessels).
• Unilateral detachment of the sensory retina at the macula occurs.
• Bilateral involvement has been reported in up to 42% of older patients (>50).
• Secondary to chorioretinopathy, it presents as an exudative neurosensory retinal detachment with or without associated RPE detachment and thick choroid.
• Commonly seen in the working-age group (25-50 y/o).

CSCR Risk Factors

• Stress.
• Type A personality.
• Male > female.
• Age: peak 20-45.
• Steroid use (oral, topical, inhaled, injection).
• Helicobacter pylori infection.
• Pregnancy.
• Ecstasy drug use.
• Idiopathic causes.
• Choroidal thickness.
• Sleep apnea.
• Erectile dysfunction drugs (e.g., Viagra).

CSCR Symptoms

• Unilateral painless vision loss (20/20-20/200).
• Color vision problems.
• Decreased contrast sensitivity.
• No relative afferent pupillary defect (RAPD).
• Increased HYPEROPIA.
• Blurring of vision, usually unilateral, perceived as a central scotoma with associated metamorphopsia and micropsia (due to photoreceptor separation).

Acute vs. Chronic CSCR

• Normal vision often restored within a few months in acute cases.
• CSCR is considered chronic if resolution does not occur after 3-4 months.
• Chronic CSCR presents as pachychoroid pigment epitheliopathy (PPE).
• PPE may be a precursor to CSCR, showing RPE disturbances similar to CSCR but without clinical/imaging evidence of acute or chronic subretinal fluid, and with thick choroid.

CSCR Signs

• Round or oval sensory retinal detachment at the macula (blister-like).
• Subretinal fluid may be clear, turbid, or fibrinous.
• Blister borders may not be well-defined.
• Starts as a pinpoint and diffuses upward, giving a "mushroom/umbrella" appearance.
  • Inkblot pattern.
  • Late changes: increase in size and brightness due to dye dispersion.

CSCR Natural Course

• Spontaneous resolution occurs in 80-90% of cases within 3-6 months.
• Visual acuity returns to 20/20 in 60% of cases.
• Recurrences occur in 40-50% of cases.
• Chronic CSCR persists for more than 1 year, typically in older patients.
• Prolonged detachment causes photoreceptor and RPE damage, leading to vision impairment.
• Some patients may develop CME, CNVM, or RPE tears.
• Rarely, bullous retinal detachment may occur secondary to CSCR.

CSCR Management

• Observation.
• Return to clinic (RTC) for follow-up every 6-8 weeks until resolved (no more than 4-6 months).
• Lifestyle modifications (stress management).
• Discontinuation of erectile dysfunction drugs (e.g., Viagra) and steroids when possible.

Laser Photocoagulation Considerations

• No resolution beyond 4-6 months has occurred.
• Recurrent CSCR.
• Bilateral CSCR.
• Patient requires immediate recovery due to occupational necessity.
• Options: focal argon laser and micropulse diode laser photocoagulation.

Photodynamic Therapy (PDT)

• Uses verteporfin, a photosensitizer that accumulates in vessels, to cause endothelial damage and vascular hypoperfusion.
• Inhibits choroidal hyperpermeability seen in CSCR.
• Studies show PDT can reduce subretinal fluid and improve BCVA in chronic CSCR patients, especially with subfoveal or diffuse leaks.
• Can be combined with intravitreal triamcinolone injections. -Meta-analysis shows no improvement in BCVA or CMT at six months with intravitreal bevacizumab (IVB) compared to control, unless coexisting with choroidal neovascularization.

When to Refer or Investigate Further

• Visual Acuity is < 20/70
• Patient is not in the typical age range
• Condition does not resolve with time, usually by 6 months
• It is getting worse instead of better
• Discrepancy between OCT and FA findings
• Unusual presentation or "doesn't smell" like CSCR

DDx For CSCR

• Pigment Epithelial Detachment (PED)
• Optic pits that lead to fluid leakage
• Coloboma
• ARMD
• Retinal Detachment

Pachychoroid Pigment Epitheliopathy (PPE)

• A slight hyperreflectivity appearing on the infrared reflectance image in the parafoveal region.
• OCT shows pachyvessels (enlargement of Haller’s layer) under the RPE and thick choroid (subfoveal choroidal thickness).

Pigment Epithelial Detachment (PED)

• Histologically, presents as separation between the RPE and Bruch membrane.
• The space may contain serous fluid, blood, drusenoid material, or a combination.
• Most frequently associated with age-related macular degeneration (ARMD).
• May involve encroachment of neovascular membranes from the choroid.
• Solitary or multiple elevated fundus lesions seen at stereoscopic clinical evaluation.
• Unlike CSCR, PED lesion angle is closer to 90 degrees. With CSCR, the angle is more acute
• May manifest with Polypoidal choroidal vasculopathy (PCV) or inflammatory etiologies

Etiologies for PED

• Inflammatory etiologies: systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), sarcoidosis.
• Bisphosphonates or pamidronate are used in the treatment of osteoporosis.
• Renal insufficiency.
• Pregnancy.
• Most likely results from outer retinal layer dysfunction in conjunction with choroidal malfunction.
• May be secondary to age-related lipid deposition leading to Bruch membrane thickening and altered choroidal permeability.

PED Diagnosis

• The FA pattern should be the same size (zona occludens tight and stays same size).
• The lesion becomes brighter over time in the same confined area (does not diffuse).

PED Management

• As with CSCR, no definitively effective treatment for serous PED has been demonstrated.
• Strategies for vascularized PED include treatments for neovascular entities, such as laser photocoagulation, photodynamic therapy, intravitreal steroids, and anti-VEGF agents.

Polypoidal Choroidal Vasculopathy (PCV) / Aneurysmal Type 1 Neovascularization (AT1)

• Idiopathic choroidal vascular disease within the spectrum of pachychoroid diseases.
• More common in African and East Asian ethnic origins and more in women than in men (5:1).
• Often bilateral but asymmetric and associated with cigarette smoking, higher BMI, and high C-reactive protein.
• Sudden onset visual loss
• Terminal swellings are frequently seen as reddish-orange nodules beneath the RPE in the peripapillary or macular area.
• Multiple PEDs are serosanguineous.
• Subretinal hemorrhages, exudates, and preretinal hemorrhages are also symptomatic.

PCV Diagnosis

• Must use ICGA to confirm the presence of swelling on the larger vessels that appear to leak
• Essential investigation: ICGA.
  • Early stages: large choroidal vessels with surrounding hypofluorescence.
  • Polyp-like swellings appear on the larger vessels and rapidly begin to leak.
  • The previously darker surrounding regions become hyperfluorescent by the late phase.
• DDx: ARMD, can co-exist

PCV Treatment

• PDT alone or in combination with anti-VEGF treatment should be the first-line treatment for sub-foveal and juxtafoveal PCV.
• PDT is often avoided in eyes with subfoveal lesions w/ good VA of 20/40 or better due to the risk of choroidal ischemia or sub-retinal hemorrhage.
• Anti-VEGF therapy alone can reduce serosanguinous complications in PCV but has limited efficacy in causing PCV complex regression.
• Laser photocoagulation may be used for extrafoveal polyps associated with subretinal hemorrhage and subretinal fluid.

Focal Choroidal Excavation (FCE)

• Most are asymptomatic and stable; though can be associated with secondary CNV, CSCR, AMD, and PCV
• Requires OCT
• Focal posterior bowing of the RPE/Bruch’s complex occurs in 2 variants.
  • Conforming FCE: the retina falls posteriorly with the RPE, and there is no gap.
  • Nonconforming FCE: the retina stays flat, and there is separation from the photoreceptors and the RPE.

FCE & CNVM

• The two conditions most associated with FCE include __________ and __________.

Management

• FCE treatment involves observation only. However, peripapillary intra-choroidal cavitation can be found adjacent to inferior edge of disc
• Treat associated CNVM or CSCR as needed and indicated.

Epiretinal Membrane (ERM)

• A fine layer of tissue that forms on the surface of the retina (inner limiting membrane).
• Contractile properties cause the underlying retina to reshape.
• Symptoms: blurred vision, metamorphopsia, macropsia, or monocular diplopia
• Occurs in 30 million adults in USA (43-86 y/o)
• Surgical removal only if severe or distorted vision

ERM Risk Factors/Etiology

• Idiopathic ERMs are the most common.
  • Posterior vitreous detachment (PVD).
    • Age: ~65 y/o
    • History of ERM in the fellow eye
• Retinal vascular diseases (diabetic retinopathy, retinal vein occlusion).
• Ocular inflammatory disease.
• Trauma
• Intraocular surgery (cataract surgery).
• Intraocular tumors.
• Retinal tear or detachment.
• VA: 20/20 - 20/200

ERM Pathogenesis

• Residual cortical vitreous after PVD or partial separation of the posterior hyaloid allows proliferation of glial cells, forming the ERM.
• Inflammatory mediators can promote fibrocellular growth, especially in secondary ERM formation.
• ERM can cause surface retinal traction, leading to lamellar macular changes, partial-thickness macular holes, and CME.
• ERM can create a pseudohole because of steepening of foveal contour from contracting ERM (no schisis cavities).

Ocular Signs

• Cellophane reflex appears early.
• Prominent membrane folds develop later.

ERM Stages

• Stage 1: thin ERMs with a foveal depression and readily distinguishable retinal layers.

• Stage 2: lack a foveal depression, show retinal distortion, and have stretching or widening of the outer nuclear layer, although retinal layers still are distinct.

• Stage 3: emergence of continuous ectopic inner foveal layers and maintenance of observable retinal layers.

• Stage 4: thick ERMs with a disrupted macula, distorted and indistinguishable retinal layers, and continuous ectopic inner foveal layers.

Diagnostics

• OCT is paramount for detecting early formation, detecting retinal folding or pseudoholes
• FA might show some leakage and vascular tortuosity.

Differential Diagnoses

• Macular hole, parafoveal telangiectasia, and macular edema must also be considered.

Treatment

• Only performed if symptomatic, or distortion
• Observe for predictive factors for visual outcome using OCT:
  • Distortion and disorganization of retinal inner layers (DRIL)- The extent of DRIL is associated w/ preoperative and postoperative visual function in eyes with ERM. Severe DRIL cases are not expected to obtain significant improvement

ERM Predictive factors

• It is more difficult to remove membranes in an eye with small "Sukima" or space between the ERM and the retinal surface where the ERM is firmly attached to the ILM. In cases such as these ERM's are easily peeled
• Disruption of EZ is more likely to be seen in eyes with small "Sukima", this damage can lead to disruption of the outer retina

ERM Treatment

• Consider surgery if symptomatic and VA worse than 20/60 or visually significant complaints occur (distortion and progressive decrease in vision).
• Vitrectomy surgery with membrane peeling using dyes like indocyanine green or brilliant blue G (BBG) can effectively stain the ILM underlying the ERM.
• Restoration of the retinal anatomic structure predominately occurs within the first 3 months post ERM peeling.

Follow-Up

• Every 1 week, then 1 month, then every 3-4 months.

Macular Holes

• Hole formation starts at the ILM and extends to the outer segment of photoreceptor layer.
• Vitreoretinal traction and PVD can also be caused by chronic inflammation

Macular Hole Etiology

• Idiopathic causes are typical relating to weak vitreous attachments
• Can be bilateral in 30%
• Higher incidence in older patients >60.

Macular Risk Factors to Development of Macular Holes

• Trauma
• Myopia
• Inflammation: CME (chronic)

Macular Hole Causes

• Vitreoretinal abnormalities can result in alterations in retinal anatomy
• Abnormal attachments between the vitreous and retina result in:
  • Single or multiple retinal adhesions
  • Alterations of the retinal Profile
    • May cause anatomical damage, especially in Vitreomacular Adhesion (VMA).

VitreoMacular Adhesion (VMA)

• Adhesion size greater than 1500 um classified as "broad"
• Adhesion size less than 1500 um classified as "focal"
• Adhesion with partial posterior vitreous detachment is Classified Vitreomacular Traction Syndrome and can cause traction

Vitreomacular Traction Syndrome

• Partial detachment of posterior hyaloid leads to change in retinal contour, distortion or formation of Pseudocyst
• Results in anatomical damage
• No full thickness interruption of layers occurs
• Pseudocyst forms and VA still remains 20/20 because ellipsoid zone is still intact
• Cotton-ball signs can be best determined with VMT & ERM

Macular Hole Staging

• Stage 1: flattening of the foveal depression with an underlying yellow spot and lack of foveal reflex (Impending macular hole); the INL detaches from PR layers
• Stage 2: small full-thickness hole <400 um with a red base and yellow-white dots; posterior hyaloid is still attached Almost 100% progress to Stage 3
• Stage 3: the premacular vitreous is still attached with surrounding grey cuff of subretinal fluid. Full Hole has a red base and yellow-white dots, underlying operculum that may be visible; VA 20/200 Full thickness measuring at 400um, operculum develops due to vitreous attachment 100% will progress to Stage 4
• Stage 4: full-size macular hole >400 um with complete PVD and Weiss ring due to no vitreous traction

Macular Hole Management

• In small stage I-II macular holes, there is a chance of spontaneous closure (4-11.5% success) and vitrectomy is recommended for large-diameter holes.
• A successful approach is: three-port pars plana vitrectomy, ILM peel, gas tamponade, and postoperative prone positioning.
• D/C tx: Jetra (Ocriplasmin) has too many SE, and is no longer preferred & now out of market
• Gas Tamponade to treat with PPV, +/- ILM peel, gas bubble, and positioning and to stain with Typan blue (TB), Brilliant blue G (BBG), Triamcinolone acetonide for identification

Dyes Used in Treatment

• Indocyanine green (ICG): for ILM identification.
• Typan blue (TB): for ERM visualization.
• Brilliant blue G (BBG): for ILM identification.
• Triamcinolone acetonide: for vitreous (HM) identification.

Gases Used in Treatment

• 18% perfluoropropane (C3F8) gas tamponade.
• Sulfur hexafluoride (SF6) Face-down positioning = traditional standard of care
• 5 days to 1 week after surgery for idiopathic macular hole repair Trending now toward minimal face down time or even none at all
• Equally successful in closure rates and end BCVA

Other newer tx: on the rise

• Autologous retinal transplantation (ART)
• Human amniotic membrane transplant (hAM)
• VPT/VPA

DDx Macular Hole

• ONH edema, papilledema.
• Lamellar hole.
• Abnormal foveal contour with a reverse anvil configuration.
• Partial-thickness holes.
• Reduction in foveal thickness is relative to the internal structures
• External retinal layers remain intact preserving vision with a intact:
• Outer nuclear layer
• External limiting membrane -EZ presence

Macular Telangiectasia (Mac Tel)

• Idiopathic juxtafoveolar retinal telangiectasis (IJRT) is a disease that occurs in the perifoveal or juxtafoveal area
• Classified in 3 groups and subgroups
• Type 2 (Perifoveal Telangiectasia) represents the most common form of IJRT with bilateral involvement and later onset

Type 1 JRT

• Individuals in this category probably have a mild form of Coats disease.
• Typically male and have a unilateral presentation that is more often localized to the macula and paramacular area than is seen in Coats Disease.
• Occurs in the patient mid-30s

Group 2 IJRT

Perifoveal Telangiectasia represents the most common form of IJRT, characterized by bilateral involvement and later onset than group 1 It is sub-grouped into 2A, acquired, and 2B, congenital

• Patients can either be male or female and usually have a bilateral presentation
• Associated w/ minimal to no lipid exudation and demonstrates superficial retinal crystals in ~50% of patients
• Pigment migration and plaque formation can be seen in the later stages

Group 3 IJRT

Extensive occlusion of the juxtapapillary network and associated w/ systemic disease

Type II Idiopathic Macular Telangiectasia (IMT)

• Has a bilateral presentation commonly associated with pigmentary intraretinal changes and vascular anomalies confined to the perifoveal region
• Although no evidence of hemorrhages or exudates is seen in Type II IMT, OCT technology often reveals associated areas of increased retinal thickness
• TEMPORAL side
• Occurs around Mean age of onset is 55 y/o and is related to smoking

Symptoms

• Can be Blurred vision, Metamorphopsia, Paracentral scotomas
• Parafoveal graying of the retina
• Superficial crystalline deposits
• Subfoveal cystoid cavities
• Parafoveal telangiectasias
• Right-angle vessels

Ocular Signs

• Superficial crystalline deposits are thought to represent the remnants of degenerated Muller cells because of their location near the ILM
• WATCH FOR TEMPORAL side
• Could be confused w/ AMD
• Draping of the ILM over cyst formation
• Central lamellar cyst is visible on OCT and a hallmark diagnostic sign

Mac Tel Diagnostics

• Correlates small nasal scotomas VF defects detected by microperimetry; with OCT
• Cavitation of the outer retina is indicative with vision loss in MacTel is
• Photoreceptor abnormality occurs early in the disorder and progression of photoreceptor cell loss may be detected on OCT

Mac Tel differentials

• DME, Pseudophakic macular edema, lamellar/macular hole, Coats disease, RVO, Radiation retinopathy, OIS, Crystalline retinopathy, and UFT Type 1 and 3
• Proliferative disease can be mistaken for choroidal neovascularization from ARMD (anti-VEGF to help)

Mac Tel Treatment

• Observation to monitor lesion
• Oral CAI helpful or non-proliferative, anti-VEGF useful for proliferative form
• Smoking should be discontinued to prevent risk factor
• Encelto is the first and only FDA-approved treatment for MacTel