Pachychoroid spectrum diseases

1. Imaging for Pachychoroid Spectrum Diseases
Yasuo Yanagi
Associate Professor Duke-NUS Medical School
Singapore National Eye Centre, Singapore Eye Research Institute

2. First “PCV” paper
was published
FFA
1991 2008
ICGA OCT
1955 1986 2013
Fundus Imaging Technologies
Time-domain OCT
EDI-OCT
Spectral-domain OCT
SS-OCT
“Pachychoroid” phenotype
was proposed

3. “Pachychoroid spectrum diseases“
• Central serous chorioretinopathy (CSCR)
• Pachychoroid neovasculopathy
– Polypoidal Choroidal Vasculopathy (PCV)
– typical (exudative) AMD
• Pachychoroid pigment epitheliopathy
• Pachydrusen?

4. “Pachy- (= thick) choroid phenotype“
1. Regional choroidal hyperpermeability on indocyanine green angiography
Reduced fundus tessellation in areas of choroidal thickening
2. Increased choroidal thickness May be diffuse or localized to focus of manifest disease
3. Pathologically dilated outer choroidal vessels (pachyvessels)
4. Club-shaped posterior-terminal morphology of pachyvessels
5. Attenuation and thinning of choriocapillaris and Sattler vessels overlying pachyvessels
Balaratnasingam et al Retina 2016
Pachychoroid phenotype
Pachychoroid should not synonymously used with “thick choroid”
Pachychoroid phenotype is associated with the development of a spectrum of clinical
diseases including CSCR, pigment epitheliopathy and neovasculopathy.
Functional and anatomical abnormalities of the choroid

5. “Pachy- (= thick) choroid phenotype“
1. Regional choroidal hyperpermeability on indocyanine green angiography
Reduced fundus tessellation in areas of choroidal thickening
2. Increased choroidal thickness May be diffuse or localized to focus of manifest disease
3. Pathologically dilated outer choroidal vessels (pachyvessels)
4. Club-shaped posterior-terminal morphology of pachyvessels
5. Attenuation and thinning of choriocapillaris and Sattler vessels overlying pachyvessels
Balaratnasingam et al Retina 2016
Pachychoroid phenotype
Pachychoroid should not synonymously used with “thick choroid”
Pachychoroid phenotype is associated with the development of a spectrum of clinical
diseases including CSCR, pigment epitheliopathy and neovasculopathy.
Functional and anatomical abnormalities of the choroid

6. Abnormal Choroidal Vascular Pattern in AMD
Bischoff and Flower 1983 Am J Ophthalmol.
Dilation of Aging
Arteries and
Arterioles
Choriocapillaris might be
subjected to a Higher than
normal blood Pressure
Distention of the
Capillaries
Exudation
Subretinal Neovascularization
ICGA

7. Choroidal Vascular hyperpermeability in CSCR
Guyer, Yannuzzi et al., Arch Ophthalmol 1994
Choroidal
hyperpermeability
Serous RPE Detachment
Mechanically induced
leak or RPE
Decompensation
RPE leakage
Neurosensory Retinal
Detachment
ICGA

8. Choroidal Vascular hyperpermeability in PCV
Choroidal vascular hyperpermeabiliity (-) Choroidal vascular hyperpermeabiliity (+)
Visualized as multifocal hyperfluoresence
in the middle and late phases
Higher prevalence of Choroidal Hyperpermeability in
eyes with PCV compared to typical AMD
PCV Typical AMD
Sasahara et al (2006) 9.8% 1.9%
Koizumi et al (2013) 34.8%
Kim et al (2015) 26.9% 12.4%
ICGA
Spaide et al., 1995 Retina

9. Clinicopathological study of PCV
Stasis of Vessels
Hyperpermeability
Edema and Degeneration
or the tissue Elevation of Tissue
Pressure
Displacement of the lesion
The lesion consisted of degenerated RPE-Bruch’s membrane-choriocapillaris
complex and inner choroid containing largely dilated venules and arterioles.
Okubo et al., Br J Ophthalmol 2001
ICGA

10. Choroidal Vascular hyperpermeability
and treatment outcomes of PCV
• Presence of choroidal vascular
hyperpermeability predisposes to poor
response to intravitreal ranibizumab, but not
to intravitreal aflibercept.
• Presence of choroidal vascular
hyperpermeability is associated with better
visual outcome, and lower injection number in
combination therapy of anti-VEGF and
photodynamic therapy.
Cho et al., AJO 2013; Koizumi et al., AJO 2013; Sonoda et al., BMC Ophthalmol 2013
Maruko et al., AJO 2013; Yanagi et al., Retina
ICGA

11. Choroidal hyperpermeability (+)
Choroidal hyperpermeability (-)
Yanagi Y et al., Retina 2017

12. Choroidal hyperpermeability (+)
Choroidal hyperpermeability (-)
Yanagi Y et al., Retina 2017

13. “Pachy- (= thick) choroid phenotype“
1. Regional choroidal hyperpermeability on indocyanine green angiography
Reduced fundus tessellation in areas of choroidal thickening
2. Increased choroidal thickness May be diffuse or localized to focus of manifest disease
3. Pathologically dilated outer choroidal vessels (pachyvessels)
4. Club-shaped posterior-terminal morphology of pachyvessels
5. Attenuation and thinning of choriocapillaris and Sattler vessels overlying pachyvessels
Balaratnasingam et al Retina 2016
Pachychoroid phenotype
Pachychoroid should not synonymously used with “thick choroid”
Pachychoroid phenotype is associated with the development of a spectrum of clinical
diseases including CSCR, pigment epitheliopathy and neovasculopathy.
Functional and anatomical abnormalities of the choroid

14. EDI-OCT
OCT
Coherencegate
Inverted mirror image
Spaide et al., Am J Ophthalmol 2008

15. Central choroidal thickness in typical AMD and PCV
normal
Typical AMD
PCV
Chung et al., Ophthalmology 2011 Koizumi et al., Graefes’. 2011 Jirarattanasopa et al., IOVS 2012
EDI-OCT
OCT

16. Choroidal thickness in typical AMD vs PCV
Typical AMD
(n = 45)
PCV
(n = 58)
Choroidalthickness(mm)
P<0.05
Yanagi Y et al., [Nippon Ganka Gakkai Zasshi 2015]
Considerable overlap
Choroidal vascular abnormalities may be associated not only with PCV but also typical AMD.
PCV Typical AMD
Sasahara et al (2006) 9.8% 1.9%
Kim et al (2015) 26.9% 12.4%
Prevalence of choroidal vascular hyperpermeability
OCT

17. Ultrawidefield imaging
Ultrawide field imaging and the choroid
EDI OCT
Ultrawide field imaging

18. Vortex vein engorgement in a case with CSC
Pang et al., AJO 2014congestion
Vortex vein engorgement and choroidal thickening
• Correlations between vortex vein
engorgement with both choroidal thickening
and choroidal vascular hyperpermeability.
• Higher prevalence of vortex vein engorgement
in eyes with PCV than in controls. Chung et al., Retina 2013
Ultrawide field imaging

19. Widespread Choroidal thickening in eyes with Choroidal
vascular hyperpermeability
(μm)
＊: P value <0.05
0
50
100
150
200
250
300
350
CVH(-) CVH(+)
0
100
200
300
400
500
CVH(-) CVH(+)
0
50
100
150
200
250
300
CVH(-) CVH(+)
0
50
100
150
200
250
300
CVH(-) CVH(+)
0
50
100
150
200
250
300
CVH(-) CVH(+)
＊
＊
＊
＊
CVH (+) (n=21) vs CVH (-) (n=31)
Nomura … Yanagi Clin Ophthalmol 2015
Ultrawide field imaging
Choroidal thickness
- at the fovea
- at four midperipheral
areas (mean choroidal
thickness at points on
6- and 9-papilla
diameter circles)

20. Choroidal hyperpermeability (+)
Choroidal hyperpermeability (-)
Yanagi Y et al., Retina 2017

21. “Pachy- (= thick) choroid phenotype“
1. Regional choroidal hyperpermeability on indocyanine green angiography
Reduced fundus tessellation in areas of choroidal thickening
2. Increased choroidal thickness May be diffuse or localized to focus of manifest disease
3. Pathologically dilated outer choroidal vessels (pachyvessels)
4. Club-shaped posterior-terminal morphology of pachyvessels
5. Attenuation and thinning of choriocapillaris and Sattler vessels overlying pachyvessels
Balaratnasingam et al Retina 2016
Pachychoroid phenotype
Pachychoroid should not synonymously used with “thick choroid”
Pachychoroid phenotype is associated with the development of a spectrum of clinical
diseases including CSCR, pigment epitheliopathy and neovasculopathy.
Functional and anatomical abnormalities of the choroid

22. Increased choroidal thickness
Normal subject
SS-OCT: en face
Swept source OCT: depth-resolved 3D analysis

23. Inner choroid
Outer choroid
Dilated
outer choroidal vessels
Normal outer choroidal vessels
SS-OCT: en face
Swept source OCT: depth-resolved 3D analysis

24. Inner choroid
Outer choroid
Attenuation and thinning of
choriocapillaris and Sattler vessels
overlying dilated choroidal vessels
SS-OCT: en face
Swept source OCT: depth-resolved 3D analysis

25. Club-shaped posterior-terminal morphology
(abrupt termination of pachyvessels)
Inner choroid
Outer choroid
SS-OCT: en face
Swept source OCT: depth-resolved 3D analysis

26. “Pachy- (= thick) choroid phenotype“
1. Regional choroidal hyperpermeability on indocyanine green angiography
Reduced fundus tessellation in areas of choroidal thickening
2. Increased choroidal thickness May be diffuse or localized to focus of manifest disease
3. Pathologically dilated outer choroidal vessels (pachyvessels)
4. Club-shaped posterior-terminal morphology of pachyvessels
5. Attenuation and thinning of choriocapillaris and Sattler vessels overlying pachyvessels
Balaratnasingam et al Retina 2016
Pachychoroid phenotype
Pachychoroid should not synonymously used with “thick choroid”
Pachychoroid phenotype is associated with the development of a spectrum of clinical
diseases including CSCR, pigment epitheliopathy and neovasculopathy.
Functional and anatomical abnormalities of the choroid

27. OCT
RPE undulation
Neovascular membrane
OCT-Angio
OCT-Angio
Pang et al., 2015 Retina
The cause of pachychoroid
neovasculopathy might be a pachychoroid-
driven process such as choroidal
congestion and choroidal
hyperpermeability manifested by choroidal
thickening and dilated choroidal vessels.
“Pachychoroid neovasculopathy” in resolved CSCR
“resolved CSC”
In CSCR, shallow irregular PED on OCT may be associated with pachychoroid
neovasculopathy than previously thought.
Attenuation and thinning of choriocapillaris
and Sattler vessels overlying pachyvessels
Thick choroid, pachyvessels

28. 33y.o. M
“Pachychoroid Pigment epitheliopathy”
Reduced fundus tessellation
Warrow et al., Retina 2013
Detailed Choroidal Structural Analysis
Pachychoroid pigment epitheliopathy may
be associated with non-exudative
neovascularization in the fellow eyes with
exudative AMD.
(Yanagi et al. IOVS in press)
Hypopigmented RPE changes
Hyperreflective material above the RPE
Luminal volume (dark area) increase

29. ChoriocapillarisOuter retina Sattler’s layer Haller’s layer
Case1
Case2
Case3
OCT
non-exudative neovascularization in the fellow eyes with exudative AMD
Detailed Choroidal Structural Analysis
Yanagi Y et al., IOVS in press
Areas of neovascularization were closely associated with:
Areas of underlying pachyvessels
Localized disturbance in choriocapillaris flow signal

30. Genetic factors associated with pachychoroid phenotype
• Increased choroidal thickness & choroidal
vascular hyperpermeability
– An association of increased subfoveal choroidal
thickness and choroidal vascular hyperpermeability
with G allele frequency in ARMS2 A69S (rs10490924)
and the T allele of CFH (rs1329428), risk alleles which
are also shared by CSCR. (Yoneyama et al Retina 2016)
• Pachychoroid neovasculopathy
– Genetic susceptibility to AMD was significantly lower
than that of exudative AMD; ARMS2 rs10490924 (p =
0.029), CFH rs800292 (p = 0.013) and genetic risk
score calculated from 11 AMD susceptibility genes (p
= 3.8 x 10-3). (Miyake et al., Sci Rep 2016)
Potential Role of Inflammatory Cytokines

31. Aqueous humor cytokines associated with
the thickened choroid
Aqueous humor
samples
(pre-cataract surgery)
Multiplex analysis
Identification of factor(s)
associated with choroidal
thickness
Factors associated with
choroidal thickness
IP-10, MCP-1, IL-6, IL-10, CXCL1,
CXCL12, CXCL13, CCL11, MMP-9
n = 76
Strategy for discovery
Potential Role of Inflammatory Cytokines

32. Aqueous humor concentration of CXCL13 is correlated
with subfoveal choroidal thickness
Nomura Y … Yanagi Y, 2015 Retina
The concentration of CXCL13 was associated with subfoveal choroidal thickness (P=0.001)
independently of axial length (P=0.049).
Potential Role of Inflammatory Cytokines

33. Negative Control CXCL13 IgG control
Nomura Y … Yanagi Y, 2015 Retina
Expression pattern of CXCL13 in the choroid
Potential Role of Inflammatory Cytokines

34. Functions of CXCL13
Disease or condition reference
Age-related macular
degeneration
Upregulated in the peripheral
blood lymphocyte
Silveira et al., Vision
Research 2010
CNV model Upregulated in the laser-induced
CNV
Fujimura et al., IOVS 2012
Angiogenesis May modulate angiogenesis by
interfering with FGF-2 activity.
Spinetti, G., et al., Biochem.
Biophys. Res.
Commun. 2001
CXCL13 has been shown to be involved in lymphomagenesis
Outside of maintaining homeostasis in lymphoid tissues, other functions for CXCL13
remain incompletely defined.
Potential Role of Inflammatory Cytokines

35. AMD, pachychoroid phenotype and CNV
CSCRpigment epitheliopathy
drusen Geographic atrophy
“Pachychoroid phenotype”
Neovascular AMD
Pachychoroid
neovasculopathy
non VEGF pathway
Genetic factors different from AMD
CNV (= typicial AMD and PCV)VEGF
“AMD”

36. Take home message
• Substantial proportion of patients with exudative
maculopathies in Asian countries are characterized by
“Pachyvessels”
• They include functional and anatomical abnormalities such
as
– Choroidal vascular hyperpermeability in ICGA
– Thickened Choroid on structural OCT
– Dilated Choroidal vessels on en face OCT
• Biological aspects of this phenotype have not been
resolved yet, but genetic factors and cytokines associated
with this phenotype is different from AMD
Dilation of Choroidal Vessels
Higher Hydrostatic
Pressure
Distention of the
Capillaries/
Ischemia
Subretinal
Neovascularization