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Overlooked and Misdiagnosed: Understanding The Disclosure Statement: Pachychoroid Nothing to disclose Spectrum RAMAN BHAKHRI, OD, FAAO ILLINOIS COLLEGE OF OPTOMETRY

SHAWN X YU, OD, FAAO WEST LA VA MBKU COLLEGE OF OPTOMETRY

Learning objectives: What are pachychoroid spectrum diseases?

Discuss the definition, anatomy, and pathophysiology of the four pachychoroid diseases A group of conditions that are characterized by choroidal thickening (pachychoroid) which can result in RPE changes and possible vision loss through complications such as . Understand, interpret, and distinguish the common signs and symptoms associated with each condition as well as some of their comorbidities. Review testing and treatment of pachychoroid disease through case analysis. While some are very rare, others are seen on a frequent basis. pachychoroid pigment epitheliopathy (PPE) central serous chorioretinopathy (CSCR) pachychoroid neovasculopathy (PNV) polypoidal choroidal vasculopathy (PCV).

Where is the love? Beyond a nevus…

•Often overlooked, but it has an important physiologic function Relevance of the Associated with many disease processes ◦ Beyond pachychoroid spectrum ◦ AMD ◦ Posterior uveal effusion • Commotio Retinae syndrome • MEWDS ◦ Many others being discovered

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Commotio Retinae: Signs and Symptoms

Opaque whitish Complications: RPE hyperplasia, RPE , CNVM, choroidal rupture,

Decreased vision, possible field defect

Commotio Retinae Background/Pathophysiology 55 yr old Japanese man presented after being hit by tennis ball OS during a match. Retinal opacification resulting from blunt ocular trauma which usually subsides in a short period, without any decrease in vision. BCVA was 20/100 in affected eye (OS) with a trumatic hyphema

When the posterior pole is affected, CR is called Berlin's edema, name derived from the initial “Later” pt’s hyphema resolved, dilated exam revealed a hypothesis of Berlin, proposing that extracellular retinal edema is responsible for the fundoscopic commotio retinae involving mac. findings.

Based on histologic data, some authors suggested that the retinal whitening resulted from intracellular edema of glial elements and retinal axons, whereas investigations performed in animals and a demonstrated that CR represents damage to the photoreceptors and retinal pigment epithelial (RPE) cells.

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1 month later

4 months later

7 months later

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Results

Series of 8 patients with commotio retinae Findings showed thickened choroid in traumatic eye vs fellow eye.

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MEWDS MEWDS

• Affects young women>men • Treatment: Observation. • Unilateral • Recover acuity loss within 10 weeks • Symptoms: • Blurred vision, , photopsias. • Sequelae: RPE mottling/depigmentation • Signs: white dots at level of RPE/outer retina, foveal granularity, disc edema, mild vitritis • Viral Etiology? • HPV • Hep A and B • Genetic? • 4/9 patients were positive for HLA-B51

MEWDS

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Subfoveal choroidal thickness in multiple evanescent white dot syndrome

MEWDS

Clinical and Experimental Optometry, Volume: 95, Issue: 2, Pages: 212-217, First published: 24 October 2011, DOI: (10.1111/j.1444-0938.2011.00668.x)

Outer Retinal and Choroidal Evaluation in Multiple Evanescent White Dot Syndrome (MEWDS): An The Final Enhanced Depth Imaging Optical Coherence Frontier! Tomography Study

One of the last places in the eye that has not been thoroughly investigated. EDI, En Face OCT/OCTA

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Choroidal Anatomy

Often ignored part of orbital anatomy. Made up of 3 primary layers ◦ Choriocapillaris - small vessels which serve to perfuse outer retina Choroidal Anatomy ◦ Sattler’s layer – medium sized vessels ◦ Haller’s layer – Large vessels, most outer part of choroid

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Choroidal Thickness Study

•Pachy-(Greek for thick)-choroid •88 subjects, 176 eyes between •Phenotypically focal or diffuse thickened choroid 20-40 • between +6.00 to •Normal range 191 to 350μm -6.00 • Dependent on age, axial length, refractive error, blood pressure, diurnal cycle • There is also some racial variations in thickness

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Diurnal Cycle Results

Measurements taken every 3 hours between 7AM and 3 groups of subjects 10PM for 2 days 64 patients from children's hospital Using partial coherence interferometry ◦ Age 3-12 ◦ (like a A-scan but done with light) 39 U Penn Employee/grad/med Fluctuation over day was 59.4 ± 24.2 μm 10 U Penn undergrads ◦ Age 18-24

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Choroidal Thickness Cont. Other discernable features

•Patients with CSC and PCV have been documented in literature to have choroidal thickness as high as 590μm •Attenuated choriocapillaris and Sattler’s layer •No particular thickness is definitive or diagnostic. •Dilated and thickened Haller’s •>300μm can be considered pathologic if characteristics consistent with pachychoroid layer disease •Hyperpermeable choroidal vessels on ICGA

•OCTA or en face – show large dilated outer choroid with abrupt change to a very shallow attenuated inner choroid.

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Patient with chronic CSC 31 32

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Expanding List

Polypoidal choroidal Central serous Pachychoroid vasculopathy Pachychoroid pigment chorioretinopathy neovasculopathy (PCV)/aneurysmal type epitheliopathy (PPE). (CSC). (PNV). 1 neovascularization (AT1).

Peripapillary Focal choroidal pachychoroid Choroidal Folds?? excavation (FCE). syndrome (PPS).

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Pachychoroid Pigment Epitheliopathy (PPE)

• Considered forme fruste to CSCR or more advanced pachy spectrum Pachychoroid • Clinical manifestations usually take on atrophic RPE changes • Mottling • RPE elevation or drusenoid lesions Pigment • RPE pigmentary changes resembling AMD • Usually appear in much younger patient than expected for AMD

Epitheliopathy (PPE) • Often misdiagnosed for dystrophies or AMD

• Etiology: thickened choroid leads to the RPE changes seen in PPE • Pt’s usually asymptomatic • Diagnosis: helpful with multimodal imaging, EDI, OCTA, FAF • Treatment: monitor

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Case

Case 1

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Case Cont

•52 year old Caucasian male •Systemic conditions remarkable for HTN, cardiomyopathy, obesity •BP is 122/65 (2/10/2019) with no medications •BCVA OD: +0.50-0.50x095 20/20 Case 2 OS: +0.75 DS 20/20

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Central serous chorioretinopathy (CSCR)

Central serous chorioretinopathy (CSCR) Risk Factor: Sleep Apnea • Signs: Localized serous RD, serous PEDS, RPE disruption, usually unilateral, guttering…. • Rare intra retinal edema..chronic Review of 458 articles, 15 included studies, 7238 pts • Symptoms: Blurred vision, metamorphopsia, central scotomas, asymptomatic CSCR patients had 1.56x more likely to have Obstructive Sleep Apnea (OSA) ◦ Moderate to severe OSA actually show thinning of subfoveal choroid • Etiology: Patients have a thick choroid, increased choroidal vascular area and increased choroidal vascular permeability. In these areas PEDs occur leading to compromise of the blood retinal barrier and localized RPE disruption with subsequent serous RD. • • Risk factors: type A personality, steroid exposure, sleep apnea, emotropic/hyperopia and pregnancy.

• Differentials: AMD, optic pit

• Treatment: monitor for self-resolution, anti-vegf, PDT, Oral Antimineralocorticoid (Spironolactone, Eplerenone etc) 54

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Smoke stack Central serous chorioretinopathy (CSCR)

•Clinical testing: • FA (ink blot, smoke stack, mushroom/umbrella pattern) • ICGA (hyperfluorescence mid phase) • FAF, OCTA, EDI

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Mushroom/umbrella Ink blot

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Treatment • Monitor for self resolution • If does not resolve by 3rd month, consider: • Anti-vegf • PDT • Oral Antimineralocorticoid (Spironolactone, Eplerenone etc) Case 3

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Case N.R. 77 year old Caucasian male Case N.R. Cont

• Diagnosed with AMD since 2009 • Pt does have Hx of smoking • Been on AREDS since diagnosis. • Systemic Hx: HTN, cholesterol, kidney disease, pacemaker, sleep apnea, DM • Meds: Amlodipine, albuterol, atorvastatin, calcitriol, AREDS 2 • BCVA: • OD: +1.75-2.50x090 20/25+ • OS: +1.00-2.25x085 20/20

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Case 4

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W.B. 94 yr old Caucasian male

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Guttering W.B. Cont

•Chronic CSC since 1970s •Hx of OHTN that converted to in the last decade • Currently on latanoprost and betaxolol OU •Systemic Hx: mitral valve disorder, HTN, anemia, BPH, kidney disease, carcinoma of bladder, rosacea •Meds: Amlodipine, supplements, finasteride, levothyroxine, losartan, tamsulosin •BCVA: OD: -1.00+2.75x002 DVA 20/25- PH NI • OS: -1.00+2.00x80 DVA CF (started with 20/150 vision 10 years ago)

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MEK Inhibitor Signs and symptoms • Signs: • Mitogen-activated protein kinase (MEK) inhibitors are medications that selectively inhibit • Fluid pockets (subretinal fluid) the mitogen-activated protein kinase cascade. This cascade is an intracellular signaling • Serous detachments pathway involved in the regulation of tumor cell proliferation which is overactive in certain • Location…. cancers, particularly • binimetinib, trametinib, and cobimetinib

• Symptoms: • Phase 1 and 2 clinical trials have noted the presence of subretinal fluid (SRF), described as a • Asymptomatic serous retinal detachment or central serous-like , in 2% to 65% of study • Reduced vision participants. • Central distortion or in central vision

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Pathophysiology MEK Retinopathy vs CSCR

• Typically, MEK patients have multifocal fluid which displays mores in the arcades • MEK inhibition causes upregulation of aquaporin 1, a membrane water • Average 6 per eye channel essential in the permeability of the RPE, leading to increased • No guttering permeability across the RPE and, thus, accumulation of SRF. • Normal choroidal thickness • pachychoroid • A retrospective case series of 25 patients showed that the median time from • No pigment epithelial detachments initiation to subretinal fluid detection was 14 days. • More likely to be bilateral • Undisturbed RPE upon resolution • Females>male

Treatment/Why is this Important Pachychoroid

• Condition itself is self limiting • Median time to resolution of subretinal fluid was 32 days. Fluid is self-limiting and does not require discontinuation of the drug. neovasculopathy

• May lead to unnecessary treatment (PNV)

• Patient and doctor education

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Pachychoroid neovasculopathy (PNV)

•Type 1 CNVM (sub RPE) over areas of pachychoroid or chronic CSC • Usually lacks drusen, younger age vs AMD • presentation may resemble wet AMD however pachychoroid appearance vs thin choroid • May have surrounding changes consistent with PPE

•88 patients with chronic CSC, followed for 1 year •Symptoms: decreased acuity, central scotoma, metamorhopsia •35.6% of their patients with chronic CSCR went on to develop Type 1

neovascularization •Etiology: Chronic pachychoroid leads to compromise of the outer blood retinal barrier, through RPE changes and PEDS, allows for formation of CNVM

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Testing

•FA •ICGA •OCT EDI •OCTA •FAF

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Treatment

•Treatment: anti-vegf • Poor efficacy for CSC • effective for PNV

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Polypoidal Choroidal Vasculopathy (PCV) Polypoidal Choroidal • First described in 1990 with exudative neurosensory detachment in peripapillary region and macula. • More female and African American/Asian predilection. • Characteristic vascular network with terminal polyps Vasculopathy (PCV) • Originates from type 1 CNVM and more recently demonstrated to be variant of type 1 CNVM. • Signs: • Polyps that can lead to • Sub retinal • Exudates • CNVM • serosanguinous PEDs • Symptoms: reduced acuity, metamorphopsia • Testing: same as PNV

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46 yr old woman, progression over 4 years

presenting Initial presentation (resolved after 3 months) En face OCTA

4 years

PED En face OCTA

PED OCTA

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Treatment The Other •PDT most common treatment. Pachychoroid •Favorable 1 year visual outcome, however high recurrence 50-60% of eyes after 1 year.

•Patients with PCV should be monitor closely after treatment indefinitely. Conditions

•Based on EVEREST II (322n) and PLANET (318n) Studies. Anti-vegf in combo with PDT was effective in regression of poylpoidal lesions. However regression still occurs at ~35- 39% 89

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Focal choroidal excavation (FCE). • Just like the title suggests, excavation in Pathophysiology choroid

• R/O staphyloma, scleral ectasia, other • Unknown at this time and is still being debated. choroidal disease. • Postulated that the defects could be congenital in nature and are due to developmental or structural defects in the choroid • postulated that pachyvessels compress the choriocapillaris causing ischemia, thinning, and • Pt’s generally asymptomatic atrophy of the inner choroid leading to focal choroidal excavation • Tend to watch • multifactorial and could be a result of traumatic, infectious, or inflammatory retinal conditions that lead to scarring of the retinal pigment epithelium and underlying choroid

• Two forms: photoreceptors attached and follows excavation vs detached.

• Present in up to 7.8% of eyes with CSC/PNV/PCV

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Conforming Non-Conforming

• The conforming subtype is characterized by the structures of the outer retina, including the • The non-conforming subtype is seen when the retinal pigment epithelium tends to follow photoreceptors and retinal pigment epithelium, directly following the contour of the cavity the contour of the cavity in the choroid. However, there is also separation of the outer in the choroid without any evidence of sub-retinal fluid. retina including, the photoreceptors, from the retinal pigment epithelium with presumable sub retinal fluid. • Reduced acuity • Conversion to CNVM

A B C Conversion

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Peripapillary pachychoroid syndrome (PPS) Findings

•New kid on the block, argued to be a distinct new variant. • Study of 31 eyes with PPS • All eyes had late FA ring like staining around disc, 48% had mild leakage •Pachychoroid around peripapillary region with usually intraretinal or • 77% had choroidal folds subretinal fluid around disc to macula. • 26% showed gravitational tracks •Generally lacks sequalae of other pachychoroid diseases. • 70% had pigmentary changes or evidence of old serous detachments •Can present similarly to uveal effusion syndrome

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Fig. 1 Case: a “sneaky” leak •79 yr old Caucasian male •Systemic Hx: obstructive sleep apnea, antiphospholipid syndrome, hypertension, hyperlipidemia •Being followed for Plaquenil •Routine OCT found SRF

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Pathophysiology

Not yet fully understood ◦ suspected choroidal congestion and elevated hydrostatic pressure. ◦ May have association with pulmonary arterial hypertension ◦ ↑ pulmonary artery pressure ◦ ↑ pulmonary vascular resistance ◦ ↑ central venous pressure ◦ ↑ hydrostatic pressure in choroid & choriocapillaris -> PPS

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Baseline, Day 1 – referred to cardiology, rtc 1 day for FA/ICGA

Case 1 day f/up – VA 20/20, symptoms resolved, ICGA revealed dilated peripapillary choroidal vessels with leakage 47 yr old woman presented to urgent care with acute onset of blurry vision +

metamorphopsia OS upon waking.

Patient had similar symptoms 1 month earlier that resolved within hours. 3 day f/up – VA 20/20, lesions returned, Pt also experiences new symptoms of shortness of breath. (orthopnea) cardiology diagnosed pt with severe precapillary No systemic history or medication use. BP measured in office 150/90 PAH and congestive heart failure. Started systemic treatment. BCVA: 20/20 OD, 20/40 OS

Anterior segment unremarkable 1 week f/up – retinal findings mostly resolved,

some fluid around ONH remains. Completely resolved at 1 month.

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Baseline 1 day

1 day f/up

3 day f/up 3 day

1 week

1 month 1 week

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Take away PAH? Other venous stasis?

• There’s spectrum choroidal induced RPE • This is first case reported in literature of PPS associated with PAH. changes, serous retinal detachment and • Other cases have been reported regarding PAH and serous detachment. neovascularization • Link between increased venous pressure and PPS? • Some mimic other macular diseases such as AMD • Yet more to learn about the choroid and retina!! • We need to understand these conditions to avoid mismanagement and mistreatment. • Test with multimodal imaging for localized choroidal thickening, vessel dilation of Haller’s layer and attenuation of inner choroid

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