Fig. 1. Enhanced depth imaging-OCT scan of a patient with pachychoroid pigment epitheliopathy (PPE). PPE changes in RPE, thick choroid, pachyveins
Fig. 2. Pachyvessels are seen in ICGA
Pachychoroid disease spectrum comprises six different groups;
1. Pachychoroid pigment epitheliopathy (PPE)
2. Central serous chorioretinopathy (CSC)
3. Pachychoroid neovasculopathy (PNV)
4. Polypoidal choroidal vasculopathy (PCV)
5. Focal choroidal excavation (FCE)
6. Peripapillar pachychoroid syndrome (PPS)
Choroidal and retinal morphology and pathogenesis
Fig. 3. Choroidal vascular congestion and late punctuate hyperfluorescence are seen at late-phase angiograms in ICGA
Fig. 4. Subretinal fluid, PED, thick choroid
In pachychoroid spectrum, dilated vessels in Haller's layer accompany to choroidal thickening, which can be detected in OCT [6].
Characteristics of dilated choroidal vessels (pachyvessels);
• In cross-sectional EDI-OCT images, large hyporeflective lumen indicates to dilated choroidal vessels (pachyvessels) [7].
• Pachyvessels can be observed within the deep choroid in en face swept source OCT images [6].
• Pachyvessels can be distinguished from normal choroidal vessels with their course on en face OCT and ICGA. Pachyvessels, unlike normal choroidal vessels, can get very closer to or cross the macula [8].
In PDS, thinning of overlying choriocapillaris and intermediate vessels within the Sattler's layer is a characteristic morphologic feature [2]. In severe cases, only abnormal dilated vessels can be observed and choriocapillaris can not be detected [4]. These patients may have a normal choroidal thickness [4]. Therefore, increased choroidal thickness should not solely be determined as a marker of PDS, morphology of choriocapillaris and Sattler's layer should be evaluated carefully.
Main blood supply of outer retina (outer nuclear layer and RPE) is choroicapillaris. Some outer retinal changes can be observed in PDS [9];
• Motling of RPE
• RPE elevation with microbreak
• Small RPE detachments
• Outer nuclear layer thinning
On ICGA, pachyvessels appear more straight and dilated than normal choroidal vessels. Choroidal hypermeability appears as patchy areas of hyperfluorescence at mid- and late-phase angiograms which is coherent with the staining areas at fluoresceine angiography [3, 10, 11]. Choroidal hyperpermeability rate was reported higher in CSC and PPE than PCV in previous studies [5]. Besides, delayed choroidal filling, choroidal vascular congestion and late punctuate hyperfluorescence can be observed with ICGA (Fig. 3). These ICGA characteristics can be observed at the fellow eyes in PDS [3, 10, 11].
The pathogenesis of choriocapillaris atrophy is stillnot clear, whether choriocapillaris atrophy is a primary condition or a consequence of tissue pressure raised from pachyvessels in Haller's layer [12]. Recent reports indicate that choriocapillaris atrophy might be the primary event, and disturbed perfusion in choriocapillaris may lead to secondary passive overflow into the large choroidal vessels which is represented as pachyvessels in Haller's layer [13-16].
Ischemic milieu due to choriocapillaris atrophy is one of the suggested mechanism for outer retinal abnormality (RPE changes and loss of functional pump capacity and outer retinal thinning) development.
• In ICGA, RPE changes corresponds to focal choroidal hyperpermeability which is suggested as a functional consequence of choroidal ischemia [10]
• In OCT, spatial distribution of RPE changes, subretinal fluid and neovascularization correlate with areas where pachyvessels and attenuated choriocapillaris localized [5]
• In optical coherence tomography angiography, choricapillaris flow impairment has been shown in eyes without RP epitheliopathy, however, impairment worsened in eyes with RP epitheliopathy [17].
Another suggested hypothesis for pachychoroid pigment epitheliopathy(PPE) and central serous chorioretinopathy (CSC) development is increased hydrostatic pressure due to choroidal hyperpermeability [9]. Increased tissue pressure is hypothesized to disrupt gap junctions between RPE cells and cause microbreaks, slight RPE detachment from Bruch's membrane due to fluid leakage and significant RPE detachment (CSR development) if leakage increases. Duration of choroidal hyperpermeability, amount of tissue pressure and alteration of resistance capacity of RPE cells are suggested as possible factors changing the clinical spectrum in this disease group [9].
Pachychoroid pigment epitheliopathy
PPE is regarded as a forme fruste of CSC [2]. Presence of microbreaks at RPE layer is suggested as initial lesions at PPE [9]. Clinical characteristics of PPE are, reduced fundus tesellation, RPE abnormalities including motling of RPE, RPE elevation, small PED, absence of soft drusen, absence of subretinal fluid, absence of subretinal fluid history, and presence of pachychoroid features [3, 18-20]. RPE features may cause misdiagnosis with age-related macular degeneration, retinal pigment epitheliitis and pattern dystrophy [6]. Fundus appearence can be observed at the fellow eyes in other PDS diseases.
The patients with PPE are generally asymptomatic. PPE appear to be a slowly progressive disease. Clnical condition may advance to CSC and these eyes may develop type 1 neovascularization without CSC development [21].
Central serous chorioretinopathy
CSC is characterized with subretinal fluid with or without PED (Fig. 4). Major predisposing factors are systemic corticosteroid and sympathomimetic use, Cushing syndrome, type A personality, hypochondria and hysteria [5, 8]. Acute form occurs generally in young to middle aged men and involves one eye. Typical imaging characteristics are dye leakage as ink-blot or smoke-stack pattern in fundus angiography (Fig. 5). Choroidal hyperpermeability (presented as hyperfluorescent patches), delayed choroidal filling and venous dilation. Increased choroidal thickness and prominent pachyvessels with choriocapillaris attenuation can be observed with OCT [22]. Acute form resolves within 4 to 6 months. Chronic CSC is defined as subretinal fluid persistence greater than 6 months. Granular hypoautofluorescence with a hyperautofluorescence margin which extends towards inferior can be seen with fundus autofluorescence (Fig.6). In addition, elongation of photoreceptor outer segments and outer retinal attenuations can be detected with OCT.
Fig. 5. Dye leakage as ink-blot pattern in fundus angiography
Fig. 6. Fundus autofluorescence (FAF) demonstrates an area of gravitational hyperautofluorescence
• Subretinal fluid usually resolves spontaneously in acute CSC, depending on symptoms and amount of subretinal fluid some cases may not need treatment
• If the patients are symptomatic or demand rapid visual gain or have poor visual acuity in the fellow eye, subthreshold micropulse laser photocoagulation, verteporfin photodynamic therapy (PDT) and systemic mineralocorticoid antagonists are recent treatment options
• Subthreshold micropulse photocoagulation (577 nm)
• effective in eyes with focal leaks [5]
• can be an option for closing leaks close to fovea [5]
• is not appear to be effective in eyes with diffuse RPE leaks [23]
• has limited effect on reducing choroidal thickness [24]
• Verteporfin PDT
• is generally used in chronic CSC
• effective for reducing the choroidal thickness [25]
• can alter intrachoroidal structures [26]
• full-dose treatment may have some adverse effects such as transient visual loss, RPE atrophy, secondary neovascularization and choroidal ischemia or infarction [5]
• therefore half-dose PDT is recently used and provides good safety and efficacy in the treatment [27-30]
• Systemic mineralocorticoid antagonists (spirinolactone-eplerenone)
• No definite effect has been demonstrated. Some randomized controlled studies have shown beneficial effects on visual gain and subretinal fluid reduction, however, it is still a debate whether visual gain and anatomic improvement are the result of treament or natural course of the disease [31-32].
Pachychoroid neovasculopathy
This entity is described as type 1 neovascularization associated with increased choroidal thickness and dilated pachyvessels in Haller's layer in the absence of age-related macular degeneration features [33]. PNV can develop in PPE and chronic CSC and may progress to PCV in some cases [34].
Type 1 neovascularization is demonstrated as shallow irregular vascularized PEDs (double-layer sign) in OCT (Fig. 7) and late leakage from undetermined source [35]. PNV areas corresponds to areas displaying pachychoroid features.
Detection rate of type 1 neovascularization within shallow PEDs appear to be low (29%) with dye-angiography, which means diagnosis rate of PNV appear to be underestimated with classical dye-angiography [37]. OCT angiography appear to be better than dye angiography in detecting type 1 neovascularization (Fig. 8). Type 1 neovascularizations can be visualized with OCT angiography as tangled networks beneath shallow PEDs [36].
Anti-VEGF agents are the standart treatment of active neovascularization [37, 38]. Treatment free interval appear to be longer in this group compared to AMD [39, 40]. Verteporfin PDT may be combined with anti-VEGF agents in refractory cases [41].
Polypoidal choroidal vasculopathy
PCV is characterized with exudative maculopathy and orange nodules with PEDs clinically [42, 43]. ICGA features were described as choroidal branching networks with polypoidal dilatations by Spaide [44]. PCV was considered as a subtype of neovascular AMD. However, eyes with PCV differentiated from classical AMD because several characteristic features of AMD such as drusen, pigmentary changes and atrophy are not common in PCV. Furthermore, EDI-OCT provided new information that these eyes have thick choroid in contrast to AMD [46]. Branching networks and polyps are identified between elevated RPE and Bruch's mebrane (indicated as a variant of type 1 neovascularization) and are correlate with the areas of pachyvessels and attenuated choriocapillaris [12, 45]. Those findings suggest that PCV is a disease in pachychoroid spectrum [45].
The role of VEGF in the pathogenesis is not fully determined. Some studies have found strong VEGF expression in endothelial and RPE cells [46, 47]. The VEGF concentration has been found lower compared to AMD, but higher than normal controls [48, 49]. In addition, elevated proinflammatory cytokine levels indicate the role of inflammation in PCV [50, 51].
Atherosclerosis and other vascular wall altreations, excess endoluminal stress due to high flow rates, high blood pressure that exceeds neovascularization capacity are suggested as pathophysiological mechanisms of polypoidal lesion development [34, 52]. Polyps are the reason of fluid exudation and hemorrhage rather than branching networks [5].
Treatment of PCV with polypoidal neovascularization
• Verteporfin PDT monotheraphy
• Has favourable visual otcomes and polyp regreression at 1 year [53, 54].
• However, 50% eyes had recurrent exudation [55].
• Intravitreal anti-VEGF monotherapy
• Ranibizumab monotherapy has lower rates of visual acuity gain and polyp regression than ranibizumab combined with verteporfin PDT [56].,
• Visual acuity gain and polyp regression rates are similar between aflibercept monotherapy and aflibercept combined with verteprofin PDT [57, 58].
• Today, intravitreal anti-VEGF therapy with/without verteporfin combination is the standart treatment regimen of PCV with polypoidal type 1 neovascularization.
Focal choroidal excavation
FCE is a choroidal concavity without a psoterior staphyloma or scleral ectasia. Clinical characteristics are good or mildly decreased visual acuity with near-normal overlying retinal structures [59]. FCE is divided into two patterns; conforming FCE described as no seperation between photoreceptors and RPE and preservation of ellipsoid zone and RPE within the lesion. Non-confirming FCE is described as detachment of photoreceptors from RPE and a hyporeflective space presumed as subretinal fluid. Increased choroidal thickness and FCE localization close to areas of choroidal hyperpermeability may suggest the association of FCE with PDS [59].
Peripapillar pachychoroid syndrome
PPS is a novel variant of PDS, which is described as pachychoroid features surround the optic nerve and associated with intra/subretinal fluid overlying pachyvessels and optic nerve edema in some patients [60]. Maximal choroidal thickness is around the optic disk rather than subfoveal localization. Most of the eyes present with serous PEDs or gravitational tracks. ICGA demonstrates dilated peripapillary pachyvessels and choroidal hyperpermeability [60].
