\set{final}

\def\Author{Green}
\def\author{green}
\def\vol{5}
\def\year{1999}
\def\page{27}
\def\txt_title{Histopathology of age-related macular degeneration}
\def\txt_authors{W. Richard Green}

\def\rcvd{24 May 1999}
\def\accept{2 November 1999}
\def\publ{3 November 1999}
\def\pdfsize{}
\def\PMID{}


\include{mvstyle.hsm}

\| External links

\def\green{http://www.wilmer.jhu.edu/greenmd.htm}

\| Internal defs

\def\Kuchle{K\uuml chle}

\article{

\title{Histopathology of age-related macular degeneration}

\authors{\hot{\green}{W. Richard Green}}

\institutions{Departments of Ophthalmology and Pathology, Johns Hopkins
Medical Institutions, Baltimore, MD}

\correspondence{W. Richard Green, MD, Johns Hopkins Hospital, 600 North
Wolfe Street, Baltimore, MD, 21287; Phone: (410) 955-3455; FAX: (410)
614-3457; email: \mailto{wrgreen@jhmi.edu}{wrgreen@jhmi.edu}}

\abstract

\p{Age-related macular degeneration is a diffuse condition involving the
retinal pigment epithelium, the photoreceptor cell layer, and perhaps
the choriocapillaris.  The early morphologic change is the development
of basal deposits of two distinct types.  This phase is not
ophthalmoscopically detectable but psychophysical testing may
demonstrate reduced function.  The process becomes detectable with the
occurence of secondary changes in the pigment epithelium, soft drusen
formation, and choroidal neovascularization.  A reparative response
results in disciform scars.  The various morphologic forms of
age-related macular degeneration are interrelated.}

\nointroduction

\p{Histopathologic and clinicopathologic correlative studies have
delineated most of the morphologic features of age-related macular
degeneration (AMD) [1-6] and the interrelationship of the various
morphologic forms [5]. \figref{1} is a flow diagram that shows the
interrelationships of the various morphologic features of AMD [6]. The
entire area centralis may be involved but the most marked changes often
occur in the central area inclusive of the parafoveal area.}

\p{The earliest morphologic feature of AMD is the development of basal
deposits external to the RPE, originally termed "diffuse drusen" [5]. It
now seems clear that two distinct types of deposits occur, basal laminar
(BLamD) and basal linear (BLinD) [1]. This terminology was put forward
in an attempt to reduce the confusion generated by previous conflicting
terms. BLamD is composed of granular material with wide-spaced collagen
located between the plasma membrane and the basal lamina of the RPE [1]
(\figref{2}). BLinD is composed of material with coated and non-coated
vesicles and some membranous profiles that is located external to the
basal lamina of the RPE, that is, in the inner collagenous zone of
Bruch's membrane (\figref{3}). This early stage of AMD may not be
evident by ophthalmoscopic examination but can be inferred by reduced
retinal function and, in some cases, by a very faint, late fluorescein
staining.}

\p{The presence of basal deposit becomes ophthalmoscopically evident by
secondary changes in the RPE, and by the development of soft drusen,
choroidal neovascularization and disciform scarring.}

\p{The RPE changes, often described as "pigment modeling," consist of RPE
attenuation with depigmentation, hypertrophy, hyperplasia and
atrophy [1,7] (\figref{4}). Accumulation of pigmented cells in the
subretinal space contributes to the appearance of clumping.}

\p{The second major feature is the development of soft (large)
drusen [1,7]. These are usually larger than nodular drusen and have
a less discrete margin. Several types of soft drusen have been observed
and include localized detachment of BLamD with or without BLinD [1].
Localized accumulation of basal linear material is emerging as the most
frequent form of soft drusen [7] (\figref{5}).}

\p{A third major feature is the development of choroidal
neovascularization (CNV), which begins in the choroid and extends into a
plane between BLamD along with RPE and the remainder of Bruch's membrane
[1] (\figref{6}). Only rarely do the vessels extend through the RPE and
into the subretinal space. In the early stages of AMD, these vessels
are capillary-like [8] (\figref{7}) and with time evolve into arteries
and veins [1,5] (\figref{8}). The number of points of origin of
choroidal CNV varies from 1 to 12. Study of serial sections throughout
the macular area of 63 eyes with CNV disclosed an average of 2.2 sources
per eye (Unpublished data, WR Green, July 1998). CNV may in turn lead to
serous and/or hemorrhagic detachment of the RPE and/or retina, pigment
modeling, exudation and RPE tears. CNV may be promoted by cellular
breakdown of Bruch's membrane (\figref{9}) [9]. This early phase of CNV
is observed in a small percentage of eyes. Most eyes with CNV are
clinically occult as defined by fluorescein angiographic features:
fluorescein leakage of undetermined origin [10] (\figref{10}) and
fibrovascular RPE detachment [11] (\figref{11}). Findings of CNV by
indocyanine green angiography include late, plaque-like staining
(\figref{12}) and a "hot spot" [12,13] (\figref{13}).}

\p{The fourth major feature is the development of disciform scarring. In
a study of a large series of disciform scars, Green and Enger [1] found
that the scar was non-vascularized in 25%, vascularized in 75%, and had
a variable histologic pattern. The scar was thin, nonvascularized and
located between the BLamD and the remainder of Bruch's membrane in 6.5%
of eyes (\figref{14}) and was a thin fibrovascular sub-RPE with BLamD in
13.2% of eyes (\figref{6}). The scar had a single subretinal component
in 32.2% of the cases (\figref{15}) and two components (subretinal and
sub-RPE with BLamD) in 48.1% of cases (\figref{16}). In those scars with
two components, the subretinal portion was larger in 47.7% of eyes, the
sub-RPE with BLamD was larger in 34.2% and the two components were about
the same size in 18.1% of the cases. Of the 231 eyes with vascularized
lesions, the new vessels were from the choroid only in 223 (96%), from
the retina and choroid in 6(2.5%) and from the retina only in 2 (0.6%).
The mean diameter and thickness of the scars was 3.73 mm and 0.44 mm,
respectively [1]. A tear of RPE and BLamD was present in 6.8% of eyes
with disciform scars [1-5] (\figref{17}). RPE and photoreceptor cell
degeneration was progressively greater as the diameter and thickness of
the disciform scar increased. Scars of 200 \mu m or more in thickness
had remaining photoreceptor cells in only about 25% of the surface over
the scar.}

\p{In two-component disciform scars, the intraBruch's membrane component
with blood vessels may extend into the subretinal component through small
defects in BLamD and any residual RPE [1,14] (\figref{18}). Larger
defects in BLamD/RPE (RPE tears) [1,2] is an additional situation in
which the two components become continuous [1,2] and blood vessels
may extend into the subretinal component from the intraBruch's membrane
component. In 8 of 310 (2.6%) of eyes with disciform scars, retinal
vessels extended into the disciform scar [1,15] (\figref{19}).}

\p{Some form of detachment was observed in 79 (10.4%) of 760 eyes with
AMD [1]. The detachments were sub-RPE with BLamD in 13 of 79 (16.5%)
eyes, serous neurosensory in 35 (44.3%), hemorrhagic neurosensory in
3 (3.8%), serosanguineous RPE in 3 (3.8%) and serosanguineous
neurosensory in 7 (8.9%). Massive hemorrhage was present in 6 eyes
(7.6%) [1] and was often associated with the use of aspirin or other
anticoagulants [1,16].}

\p{RPE atrophy was present in 282 (37.1%) of 760 eyes [1]. Of the
282 eyes, areolar atrophy was associated with disciform scars in 95
(33.7%). Atrophy was unassociated with disciform scars in 187
(24.6%) of 760 eyes. Twenty-one (11.2%) of the 187 eyes with areolar
atrophy (2.8% 760 eyes) had no disciform scarring or neovascularization
(\figref{20}). This form of AMD has been referred to as the "dry
form" of AMD. BLamD, BLinD and soft drusen are often present in such
eyes.}

\p{The various morphologic forms of AMD are a continuum. Points of
therapeutic intervention include prevention with micronutrients,
antioxidants, and reduced light exposure [17]; antiangiogenesis;
destruction of CNV [8,18-23]; antiinflammatory agents; surgical
removal of membranes [24-27]; and macular translocation [28]. The
morphologic features of AMD give little hope that surgery (submacular
membranectomy) will be of much benefit.}

\acknowledgements

\p{Supported in part by the Independent Order of Odd Fellows,
Winston-Salem, NC and the Macula Foundation, New York, NY.}

\references

\p{1. Green WR, Enger C. Age-related macular degeneration
histopathologic studies. The 1992 Lorenz E. Zimmerman Lecture.
Ophthalmology 1993; 100:1519-35. \pubmed{7692366}}

\p{2. Green WR, McDonnell PJ, Yeo JH. Pathologic features of senile
macular degeneration. Ophthalmology 1985; 92:615-27. \pubmed{2409504}}

\p{3. Green WR. Retina. In: Spencer WH, editor. Ophthalmic pathology: an
atlas and textbook. 4th ed. Vol 3. Philadelphia: W. B. Saunders; 1996.
p. 982-1050.}

\p{4. Green WR, Schwartz DM. Aspects histopathologiques. In: Coscas G,
editor. Degenerescences maculaires acquises liees a l'age et
neovaisseaux sous-retiniens. Paris: Masson; 1991. p. 90-119.}

\p{5. Green WR, Key SN 3d. Senile macular degeneration: a
histopathologic study. Trans Am Ophthalmol Soc 1977; 75:180-254.
\pubmed{613523}}

\p{6. Green WR. Age-related macular degeneration. In: Franklin RM,
editor. Retina and vitreous: proceedings of the Symposium on Retina and
Vitreous, New Orleans, LA, USA, March 12-15, 1992. New York: Kugler;
1993. p. 7-13.}

\p{7. Bressler NM, Silva JC, Bressler SB, Fine SL, Green WR.
Clinicopathologic correlation of drusen and retinal pigment epithelial
abnormalities in age-related macular degeneration. Retina 1994;
14:130-42. \pubmed{8036323}}

\p{8. Schneider S, Greven CM, Green WR. Photocoagulation of well-defined
choroidal neovascularization in age-related macular degeneration:
clinicopathologic correlation. Retina 1998; 18:242-50. \pubmed{9654416}}

\p{9. Dastgheib K, Green WR. Granulomatous reaction to Bruch's membrane
in age-related macular degeneration. Arch Ophthalmol 1994; 112:813-8.
\pubmed{7516148}}

\p{10. Small ML, Green WR, Alpar JJ, Drewry RE. Senile macular
degeneration. A clinicopathologic correlation of two cases with
neovascularization beneath the retinal pigment epithelium. Arch
Ophthalmol 1976; 94:601-7. \pubmed{1267640}}

\p{11. Bressler SB, Silva JC, Bressler NM, Alexander J, Green WR.
Clinicopathologic correlation of occult choroidal neovascularization in
age-related macular degeneration. Arch Ophthalmol 1992; 110:827-32.
\pubmed{1375826}}

\p{12. Chang TS, Freund KB, de la Cruz Z, Yannuzzi LA, Green WR.
Clinicopathologic correlation of choroidal neovascularization
demonstrated by indocyanine green angiography in a patient with
retention of good vision for almost four years. Retina 1994; 14:114-24.
\pubmed{7518604}}

\p{13. Green WR, \Kuchle\ M. Histopathologic studies of choroidal
neovascularization. In: Yannuzzi LA, Flower RW, Slakter JS, editors.
Indocyanine green angiography. St. Louis: Mosby; 1997. p. 151-6.}

\p{14. Green WR, Harlan Jr JB. Histopathologic features. In: Berger JW,
Fine SL, Maguire MG, editors. Age-related macular degeneration. St.
Louis: Mosby; 1999. p. 81-154.}

\p{15. Green WR, Gass JD. Senile disciform degeneration of the macula.
Retinal arterialization of the fibrous plaque demonstrated clinically
and histopathologically. Arch Ophthalmol 1971; 86:487-94.
\pubmed{5114441}}

\p{16. el Baba F, Jarrett WH 2d, Harbin TS Jr, Fine SL, Michels RG,
Schachat AP, Green WR. Massive hemorrhage complicating age-related
macular degeneration. Clinicopathologic correlation and role of
anticoagulants. Ophthalmology 1986; 93:1581-92. \pubmed{2433658}}

\p{17. Harlan JB, Weidenthal DT, Green WR. Histologic study of a
shielded macula. Retina 1997; 17:232-8. \pubmed{9196935}}

\p{18. Meyer D, Harris WP, Fine SL, Green WR. Clinicopathologic
correlation of argon-laser photocoagulation of an idiopathic choroidal
neovascular membrane in the macula. Retina 1984; 4:107-14.
\pubmed{6205429}}

\p{19. Guyer DR, Fine SL, Murphy RP, Green WR. Clinicopathologic
correlation of krypton and argon laser photocoagulation in a patient
with a subfoveal choroidal neovascular membrane. Retina 1986; 6:157-63.
\pubmed{2432637}}

\p{20. Grossniklaus HE, Frank RE, Green WR. Subretinal
neovascularization in a pseudophakic eye treated with krypton laser
photocoagulation. A clinicopathologic case report. Arch Ophthalmol 1988;
106:78-81. \pubmed{2447858}}

\p{21. Schwartz D, Green WR. Clinicopathologic correlation of treated
choroidal neovascular membranes. In: Gitter KA, Schatz H, Yannuzzi LA,
McDonald HR, editors. Laser photocoagulation of retinal disease. San
Francisco: Pacific Medical Press; 1988. p. 143-67.}

\p{22. Green WR. Clinicopathologic studies of treated choroidal
neovascular membranes. A review and report of two cases. Retina 1991;
11:328-56. \pubmed{1720565}}

\p{23. Dastgheib K, Bressler SB, Green WR. Clinicopathologic correlation
of laser lesion expansion after treatment of choroidal
neovascularization. Retina 1993; 13:345-52. \pubmed{7509504}}

\p{24. Bynoe LA, Chang TS, Funata M, Del Priore LV, Kaplan HJ, Green WR.
Histopathologic examination of vascular patterns in subfoveal
neovascular membranes. Ophthalmology 1994; 101:1112-7. \pubmed{7516517}}

\p{25. Hsu JK, Thomas MA, Ibanez H, Green WR. Clinicopathologic studies
of an eye after submacular membranectomy for choroidal
neovascularization. Retina 1995; 15:43-52. \pubmed{7538690}}

\p{26. Rosa RH, Thomas MA, Green WR. Clinicopathologic correlation of
submacular membranectomy with retention of good vision in a patient with
age-related macular degeneration. Arch Ophthalmol 1996; 114:480-7.
\pubmed{8602790}}

\p{27. Grossniklaus HE, Green WR. Histopathologic and ultrastructural
findings of surgically excised choroidal neovascularization. Submacular
Surgery Trials Research Group. Arch Ophthalmol 1998; 116:745-9.
\pubmed{9639442}}

\p{28. de Juan E Jr, Loewenstein A, Bressler NM, Alexander J.
Translocation of the retina for management of subfoveal choroidal
neovascularization II: a preliminary report in humans. Am J Ophthalmol
1998; 125:635-46. \pubmed{9625547}}

\endreferences

}

\beginfigures

\figfile{1}{
\figtitle{1}{Flow diagram illustrates the relationships of the various
morphologic forms of age-related macular degeneration}

\p{Age-related macular degeneration is a diffuse
process that involves the RPE, photoreceptor cells and perhaps the
choroidal vasculature.  The first morphologic features is the development
of basal deposits.  Unfortunately, this phase only becomes evident with the
effects on adjacent tissues including:  pigment mottling with RPE clumping,
attenuation, hypertrophy, hyperplasia, and atrophy; soft drusen; RPE
detachment; and choroidal neovascularization.  Choroidal neovascularization
may then lead to serous and/or hemorrhagic detachment of the RPE and/or the
neurosensory retina, pigment mottling, exudation, hemorrhage, and RPE tears.
These features lead to a reparative process--a disciform scar that usually
has subretinal and sub-RPE components.  Disciform scars may have vascular
contributions from the retina, marked exudation, and contribute to RPE tears.}

\ctr{\gifimage{1}{666}{339}{45}}

\block{Figure 1 reprinted with permission, from: Green WR. Age-related
macular degeneration. In: Franklin RM, editor. Retina and vitreous:
proceedings of the Symposium on Retina and Vitreous, New Orleans, LA,
USA, March 12-15, 1992. New York: Kugler; 1993. p. 7-13.}

}

\figfile{2}{
\figtitle{2}{Basal laminar deposit}

\p{\panel{A}. Phase contrast appearance of BlamD with serrated inner
margin. (x9,900).}

\ctr{\jpgimage{2a}{500}{328}{64}}

\p{\panel{B}. Thick layer of basal laminar deposit is located between
the plasma (PM) and basal lamina (arrowhead) of the RPE and consists of
membrano-granular material (circle) and foci of wide-spaced collagen
(arrows). Splitting (asterisk) has occurred in this new, thick layer.
Brackets mark the elastic tissue layer of Bruch's membrane. (x50,000).}

\ctr{\jpgimage{2b}{510}{700}{124}}

\block{Figure 2B reprinted with permission, from: Green WR, Key SN 3d.
Senile macular degeneration: a histopathologic study. Trans Am
Ophthalmol Soc 1977; 75:180-254.}

\p{\panel{C}. Membrano-granular material (x29,000). \panel{D}.
Wide-spaced collagen (x29,000).}

\ctr{\jpgimage{2cd}{503}{498}{110}}

\block{Figures 2C-D reprinted with permission, from: Green WR, Key SN 3d.
Senile macular degeneration: a histopathologic study. Trans Am
Ophthalmol Soc 1977; 75:180-254.}

}

\figfile{3}{
\figtitle{3}{Basal linear deposit}

\p{\panel{A}. Ultrastructural appearance of a 6.4 \mu m-thick basal linear
deposit composed of vesicular material (asterisks) located between
the retinal pigment epithelial basal lamina (arrowhead) and the
remainder of Bruch's membrane. A 2.2 \mu m-thick layer of wide-spaced
collagen (basal laminar deposit, between arrows) is present
internal to the retinal pigment epithelial basal lamina (arrowhead).
x15,000.}

\ctr{\jpgimage{3a}{637}{803}{216}}

\block{Figure 3A reprinted with permission, from: Green WR, Enger C.
Age-related macular degeneration histopathologic studies. The 1992
Lorenz E. Zimmerman Lecture. Ophthalmology 1993; 100:1519-35.}

\p{\panel{B}. Higher power view of vesicular material in basal linear
deposit (x40,000).}

\ctr{\jpgimage{3b}{495}{295}{51}}

\block{Figure 3B reprinted with permission, from: Green WR, Enger C.
Age-related macular degeneration histopathologic studies. The 1992
Lorenz E. Zimmerman Lecture. Ophthalmology 1993; 100:1519-35.}

\p{\panel{C}. Higher power view of basal laminar deposit with foci of
wide-spaced collagen located internal to the RPE basal lamina
(arrowhead). (x40,000)}

\ctr{\jpgimage{3c}{494}{412}{54}}

\block{Figure 3C reprinted with permission, from: Green WR, Enger C.
Age-related macular degeneration histopathologic studies. The 1992
Lorenz E. Zimmerman Lecture. Ophthalmology 1993; 100:1519-35.}

}

\figfile{4}{
\figtitle{4}{Retinal pigment epithelial changes}

\p{\panel{A} \and\ \panel{B}. Ophthalmoscopic and early-phase angiogram
showing some large drusen with slight staining (brackets). Mottled
areas of hypopigmentation demonstrate more persistent staining (H), and
focal areas of hyperpigmentation show blocked fluorescence
(arrowheads).}

\p{\panel{A}.}

\ctr{\jpgimage{4a}{375}{343}{23}}

\block{Figure 4A reprinted with permission, from: Bressler NM, Silva JC,
Bressler SB, Fine SL, Green WR. Clinicopathologic correlation of drusen
and retinal pigment epithelial abnormalities in age-related macular
degeneration. Retina 1994; 14:130-42.}

\p{\panel{B}.}

\ctr{\jpgimage{4b}{517}{359}{27}}

\block{Figure 4B reprinted with permission, from: Bressler NM, Silva JC,
Bressler SB, Fine SL, Green WR. Clinicopathologic correlation of drusen
and retinal pigment epithelial abnormalities in age-related macular
degeneration. Retina 1994; 14:130-42.}

\p{Histopathologic study of the area of BlamD has RPE attenuation with
partial loss of photoreceptor cells (\panel{C}), an area of RPE and
photoreceptor cell atrophy (\panel{D}), and an area with a clump of
pigmented cells (\panel{E}). (periodic acid Schiff: \panel{C} \and\
\panel{D}, x25; \panel{E}, x40)}

\p{\panel{C}.}

\ctr{\jpgimage{4c}{500}{339}{48}}

\block{Figure 4C reprinted with permission, from: Bressler NM, Silva JC,
Bressler SB, Fine SL, Green WR. Clinicopathologic correlation of drusen
and retinal pigment epithelial abnormalities in age-related macular
degeneration. Retina 1994; 14:130-42.}

\p{\panel{D}.}

\ctr{\jpgimage{4d}{524}{353}{53}}

\block{Figure 4D reprinted with permission, from: Bressler NM, Silva JC,
Bressler SB, Fine SL, Green WR. Clinicopathologic correlation of drusen
and retinal pigment epithelial abnormalities in age-related macular
degeneration. Retina 1994; 14:130-42.}

\p{\panel{E}.}

\ctr{\jpgimage{4e}{524}{353}{43}}

\block{Figure 4E reprinted with permission, from: Bressler NM, Silva JC,
Bressler SB, Fine SL, Green WR. Clinicopathologic correlation of drusen
and retinal pigment epithelial abnormalities in age-related macular
degeneration. Retina 1994; 14:130-42.}


}

\figfile{5}{
\figtitle{5}{Soft druse from the localized accumulation of basal linear
deposit}

\p{\panel{A}. Soft drusen from localized basal linear vesicular material
(between arrows and \panel{C}) located between the retinal pigment
epithelial and the remainder of the Bruch's membrane. A thin layer of
basal laminar deposit (between arrowheads and \panel{B}) is present
between the intact RPE and the RPE basal lamina (BL). The detachment of
the basal linear deposit (asterisk) is probably artifact
(cc=choriocapillaries). x2,800.}

\ctr{\jpgimage{5a}{502}{505}{94}}

\block{Figure 5A reprinted with permission, from: Green WR, Enger C.
Age-related macular degeneration histopathologic studies. The 1992
Lorenz E. Zimmerman Lecture. Ophthalmology 1993; 100:1519-35.}

\p{\panel{B}. Higher power of basal laminar deposit with widespaced
collagen that has a periodicity of 100 nm. x40,000.}

\ctr{\jpgimage{5b}{500}{291}{38}}

\block{Figure 5B reprinted with permission, from: Green WR, Enger C.
Age-related macular degeneration histopathologic studies. The 1992
Lorenz E. Zimmerman Lecture. Ophthalmology 1993; 100:1519-35.}

\p{\panel{C}. Higher power of basal linear deposit with granular and
vesicular material. x19,000.}

\ctr{\jpgimage{5c}{500}{298}{49}}

\block{Figure 5C reprinted with permission, from: Green WR, Enger C.
Age-related macular degeneration histopathologic studies. The 1992
Lorenz E. Zimmerman Lecture. Ophthalmology 1993; 100:1519-35.}

}

\figfile{6}{
\figtitle{6}{Early choroidal neovascularization}

\p{Examples of thin subretinal pigment epithelial fibrovascular
membranes (asterisks) located between the layer of basal laminar deposit
(arrows) and Bruch's membrane. The retinal pigment epithelium is intact,
with moderate photoreceptor cell degeneration present (Van de Grift,
x40)}

\ctr{\jpgimage{6a}{526}{348}{70}}

\p{\sp}

\ctr{\jpgimage{6b}{526}{339}{74}}

\block{Figure 6 reprinted with permission, from: Green WR, Enger C.
Age-related macular degeneration histopathologic studies. The 1992
Lorenz E. Zimmerman Lecture. Ophthalmology 1993; 100:1519-35.}

}

\figfile{7}{
\figtitle{7}{Early choroidal neovascularization}

\p{Examples of choroidal neovascularization with capillaries (asterisks)
extending through defects in Bruch's membrane (between arrows) and into the
plane between RPE and Bruch's membrane (periodic acid-Schiff, x40).}

\ctr{\jpgimage{7a}{526}{348}{31}}

\p{\sp}

\ctr{\jpgimage{7b}{525}{342}{43}}

\block{Figure 7 (lower) reprinted with permission, from: Green WR, Enger
C. Age-related macular degeneration histopathologic studies. The 1992
Lorenz E. Zimmerman Lecture. Ophthalmology 1993; 100:1519-35.}

}

\figfile{8}{
\figtitle{8}{Choroidal neovascularization}

\p{\panel{A}. Area where a choroidal artery (asterisk) extends through a
defect in Bruch's membrane and into a plane between BlamD (arrowhead)
and the remainder of Bruch's membrane. (periodic acid-Schiff, x16)}

\ctr{\jpgimage{8a}{525}{342}{63}}

\block{Figure 8A reprinted with permission, from: Green WR, Enger C.
Age-related macular degeneration histopathologic studies. The 1992
Lorenz E. Zimmerman Lecture. Ophthalmology 1993; 100:1519-35.}

\p{\panel{B}. Area where a choroidal artery (A) and vein (V) extends
through a defect in Bruch's membrane (between arrows) and into a plane
between BlamD with RPE and the remainder of Bruch's membrane. (periodic
acid-Schiff, x160)}

\ctr{\jpgimage{8b}{525}{342}{70}}

\block{Figure 8B reprinted with permission, from: Green WR, Enger C.
Age-related macular degeneration histopathologic studies. The 1992
Lorenz E. Zimmerman Lecture. Ophthalmology 1993; 100:1519-35.}

}

\figfile{9}{
\figtitle{9}{Cellular breakdown of Bruch's membrane}

\p{Granulomatous reaction to Bruch's membrane with multinucleated giant
cells apparently engulfing a margin of Bruch's membrane.}

\p{\panel{A}. Van de Grift, x25.}

\ctr{\jpgimage{9a}{525}{335}{40}}

\block{Figure 9A reprinted with permission, from: Dastgheib K, Green WR.
Granulomatous reaction to Bruch's membrane in age-related macular
degeneration. Arch Ophthalmol 1994; 112:813-8.}

\p{\panel{B}. Periodic acid Schiff, x40.}

\ctr{\jpgimage{9b}{525}{344}{29}}

}

\figfile{10}{
\figtitle{10}{Occult choroidal neovascularization}

\p{\panel{A}. Ophthalmoscopic appearance of area of pigment modeling
contiguous with an inferior area of RPE detachment. \panel{B}.
Fluorescein angiographic appearance of lacy late staining superior and a
serous RPE detachment inferiorly.}

\ctr{\jpgimage{10ab}{534}{354}{38}}

\block{Figures 10A-B reprinted with permission, from: Small ML, Green WR, Alpar JJ,
Drewry RE. Senile macular degeneration. A clinicopathologic correlation
of two cases with neovascularization beneath the retinal pigment
epithelium. Arch Ophthalmol 1976; 94:601-7.}

\p{\panel{C}. Area where a choroidal vessels (asterisks) extends through a
defect in Bruch's membrane and into a plane located between BlamD with
RPE and the remainder of Bruch's membrane (Verfoeff van Geisen, x40)}

\ctr{\jpgimage{10c}{518}{339}{28}}

\block{Figures 10C reprinted with permission, from: Small ML, Green WR, Alpar JJ,
Drewry RE. Senile macular degeneration. A clinicopathologic correlation
of two cases with neovascularization beneath the retinal pigment
epithelium. Arch Ophthalmol 1976; 94:601-7.}

}

\figfile{11}{
\figtitle{11}{Occult choroidal neovascularization}

\p{\panel{A}. Red-free photograph of right macula showing subretinal
fluid surrounded by lipid (arrows), overlying apparent choroidal
neovascularization.}

\ctr{\jpgimage{11a}{440}{354}{36}}

\block{Figures 11A reprinted with permission, from: Bressler SB, Silva
JC, Bressler NM, Alexander J, Green WR. Clinicopathologic correlation of
occult choroidal neovascularization in age-related macular degeneration.
Arch Ophthalmol 1992; 110:827-32.}

\p{\panel{B}. Angiogram demonstrates occult choroidal neovascularization
with staining of irregularly elevated area of retinal pigment epithelium
and poorly demarcated leakage in the late phase in which the exact
boundaries of the neovascularization cannot be determined with
certainly.}

\ctr{\jpgimage{11b}{440}{350}{26}}

\block{Figures 11B reprinted with permission, from: Bressler SB, Silva
JC, Bressler NM, Alexander J, Green WR. Clinicopathologic correlation of
occult choroidal neovascularization in age-related macular degeneration.
Arch Ophthalmol 1992; 110:827-32.}

\p{\panel{C}. Area of fluorescein staining corresponds to a 100 \mu
m-thick scar with a 10 \mu m non-vascularized subretinal and 90 \mu m
vascularized intraBruch's membrane components. Periodic acid Schiff,
x25.}

\ctr{\jpgimage{11c}{526}{352}{90}}

\block{Figures 11C reprinted with permission, from: Bressler SB, Silva
JC, Bressler NM, Alexander J, Green WR. Clinicopathologic correlation of
occult choroidal neovascularization in age-related macular degeneration.
Arch Ophthalmol 1992; 110:827-32.}

\p{\panel{D}. Area shows a single source of neovascularization
(asterisk) from the choroid through a defect in Bruch's membrane (between
arrows). Periodic acid Schiff, 40.}

\ctr{\jpgimage{11d}{528}{346}{67}}

\block{Figures 11D reprinted with permission, from: Bressler SB, Silva
JC, Bressler NM, Alexander J, Green WR. Clinicopathologic correlation of
occult choroidal neovascularization in age-related macular degeneration.
Arch Ophthalmol 1992; 110:827-32.}

}

\figfile{12}{
\figtitle{12}{Occult choroidal neovascularization}

\p{\panel{A}. Late-phase indocyanine green angiogram demonstrating a
well-delineated area of hyperfluorescence consistent with a plaque of
CNV.}

\ctr{\jpgimage{12a}{416}{381}{34}}

\block{Figures 12A reprinted with permission, from: Chang TS, Freund KB,
de la Cruz Z, Yannuzzi LA, Green WR. Clinicopathologic correlation of
choroidal neovascularization demonstrated by indocyanine green
angiography in a patient with retention of good vision for almost four
years. Retina 1994; 14:114-24.}

\p{\panel{B}. Late staining plaque corresponds to an area of CNV located
between BlamD with RPE and the remainder of Bruch's membrane.}

\ctr{\jpgimage{12b}{534}{348}{78}}

\p{\panel{C}. One of 6 sources of neovascularization from the choroid.}

\ctr{\jpgimage{12c}{531}{348}{65}}

\block{Figures 12C reprinted with permission, from: Chang TS, Freund KB,
de la Cruz Z, Yannuzzi LA, Green WR. Clinicopathologic correlation of
choroidal neovascularization demonstrated by indocyanine green
angiography in a patient with retention of good vision for almost four
years. Retina 1994; 14:114-24.}

}

\figfile{13}{
\figtitle{13}{Indocyanine green hot spot}

\p{\panel{A}. Preoperative clinical photograph demonstrating subretinal
hemorrhage in the macular area. The inferior portion of the extravasated
blood has lost its hemoglobin, resulting in the color change.}

\ctr{\jpgimage{13a}{466}{416}{49}}

\| Permission and source documented in image

\p{\panel{B}. Late-phase indocyanine green angiogram demonstrating
blocked fluorescence from the thicker layers of hemorrhage. A more
extensive superior area of hyperfluorescence corresponds to an area of
occult CNV. In addition, a linear area of more intense hyperfluorescence
just nasal to the blocked fluorescence is consistent with a site of
neovascularization ("hot spot").}

\ctr{\jpgimage{13b}{395}{436}{45}}

\| Permission and source documented in image

\p{\panel{C}. Submacular membranectomy specimen with basal laminar
deposit (arrows) and numerous blood vessels (asterisks).
Paraphylenediamine, phase contrast, x544.}

\ctr{\jpgimage{13c}{400}{413}{82}}

\| Permission and source documented in image

}

\figfile{14}{
\figtitle{14}{Sub-RPE disciform scar}

\p{Example of thin, non-vascularized, subretinal pigment
epithelial fibrocellular disciform scars (asterisk) located between
basal laminar deposit (arrow) and the remainder of Bruch's membrane.
The retinal pigment epithelium and photoreceptor cell layer are atrophic
over the scar. Periodic acid-Schiff, x25.}

\ctr{\jpgimage{14}{526}{343}{50}}

\block{Figure 14 reprinted with permission, from: Green WR, Enger C.
Age-related macular degeneration histopathologic studies. The 1992
Lorenz E. Zimmerman Lecture. Ophthalmology 1993; 100:1519-35.}

}

\figfile{15}{
\figtitle{15}{Subretinal disciform scar}

\p{Disciform scar with single, subretinal component (asterisk). The
scar is located internal to a layer of BlamD (arrow). Periodic
acid-Schiff, x25.}

\ctr{\jpgimage{15}{500}{316}{64}}

\block{Figure 15 reprinted with permission, from: Green WR, Enger C.
Age-related macular degeneration histopathologic studies. The 1992
Lorenz E. Zimmerman Lecture. Ophthalmology 1993; 100:1519-35.}

}

\figfile{16}{
\figtitle{16}{Two-component disciform scar}

\p{Two-component disciform scar with the thin subretinal component
(asterisk) and thicker intra-Bruch's membrane component (two asterisks)
that are separated by a thick layer of BlamD (arrow) with some residual
RPE. Periodic acid-Schiff, x25.}

\ctr{\jpgimage{16}{526}{350}{85}}

}

\figfile{17}{
\figtitle{17}{Disciform scar with tear of RPE and BlamD}

\p{\panel{A}. A tear of RPE and BlamD (between arrows) is present at the
nasal margin of a two-component disciform scar. Periodic acid-Schiff,
x2.5.}

\ctr{\jpgimage{17a}{523}{338}{58}}

\block{Figure 17A reprinted with permission, from: Green WR, Enger C.
Age-related macular degeneration histopathologic studies. The 1992
Lorenz E. Zimmerman Lecture. Ophthalmology 1993; 100:1519-35.}

\p{\panel{B}. Higher power view of the RPE/BLamD tear where the nasal
margin of the tear has pulled under temporally (arrows) and the area of
the tear is filled in by fibrous tissue. Periodic acid-Schiff, x25.}

\ctr{\jpgimage{17b}{526}{351}{74}}

\block{Figure 17B reprinted with permission, from: Green WR, Enger C.
Age-related macular degeneration histopathologic studies. The 1992
Lorenz E. Zimmerman Lecture. Ophthalmology 1993; 100:1519-35.}

}

\figfile{18}{
\figtitle{18}{Choroidal neovascularization}

\p{\panel{A}.  A two-component, 100 \mu m maximal thickness, disciform scar
with a small subretinal component (single asterisk) and a small area of
serous detachment of the macula (arrowhead). There is moderate to total
loss of the photoreceptor cell layer over the scar, which is most marked over
the thicker intra-Bruch's membrane component (double asterisk).
(periodic acid-Schiff; x35).}

\ctr{\jpgimage{18a}{500}{361}{38}}

\block{Figure 18A reprinted with permission, from: Green WR, Enger C.
Age-related macular degeneration histopathologic studies. The 1992
Lorenz E. Zimmerman Lecture. Ophthalmology 1993; 100:1519-35.}

\p{\panel{B}. Higher power view of the vascularized
intra-Bruch's membrane (BM) component (double asterisk) where the basal
laminar deposit has a typical brush-like inner surface and a defect
(between arrows) where a capillary (arrowheads) extends from the
intra-Bruch's membrane component to the thin subretinal component (Van de
Grift; x360).}

\ctr{\jpgimage{18b}{500}{347}{30}}

\block{Figure 18B reprinted with permission, from: Green WR, Enger C.
Age-related macular degeneration histopathologic studies. The 1992
Lorenz E. Zimmerman Lecture. Ophthalmology 1993; 100:1519-35.}

}

\figfile{19}{
\figtitle{19}{Retinal vascularization of disciform scar}

\p{Low (\panel{A}) and higher power view (\panel{B}) of a two-component,
289 \mu m maximal thickness, disciform scar with marked to total atrophy
of the photoreceptor cell layer. The subretinal component (single
asterisk) is vascularized by a vessel (arrow) from the retina. A 7.1 \mu
m-thick layer of basal laminar deposit (arrowhead) separates the
subretinal (single asterisk) and intra-Bruch's membrane (double
asterisk) components of the scar. The intra-Bruch's membrane component
is vascularized by an artery and vein from the choroid at a different
level. Periodic acid-Schiff: \panel{A}, x45; \panel{B}, x155.}

\p{\ctr{\jpgimage{19a}{500}{332}{37}}}

\block{Figure 19A reprinted with permission, from: Green WR, Enger C.
Age-related macular degeneration histopathologic studies. The 1992
Lorenz E. Zimmerman Lecture. Ophthalmology 1993; 100:1519-35.}

\p{\ctr{\jpgimage{19b}{500}{326}{18}}}

\block{Figure 19B reprinted with permission, from: Green WR, Enger C.
Age-related macular degeneration histopathologic studies. The 1992
Lorenz E. Zimmerman Lecture. Ophthalmology 1993; 100:1519-35.}

}

\figfile{20}{
\figtitle{20}{Central areolar retinal pigment epithelial atrophy}

\p{\panel{A}.  There is total retinal pigment epithelial and
photoreceptor cell atrophy in a central 2 mm area (between arrows). 
Basal laminar deposit has been lost in a 1 mm central area (asterisk and
\panel{B}).  Basal laminar deposit remains in the peripheral zone of the
area of areolar RPE atrophy (between arrowheads and arrows and
\panel{C}).  Outside the area of RPE areolar atrophy (to either side of
arrows and \panel{D}), the RPE and photoreceptors are intact and basal
laminar deposit (arrow in \panel{D}) is present (periodic acid-Schiff:
\panel{A}, x10; \panel{B}, \panel{C}, and \panel{D}, x40).}

\p{\panel{A}}

\ctr{\jpgimage{20a}{526}{338}{43}}

\block{Figure 20A reprinted with permission, from: Green WR, Enger C.
Age-related macular degeneration histopathologic studies. The 1992
Lorenz E. Zimmerman Lecture. Ophthalmology 1993; 100:1519-35.}

\p{\panel{B}}

\ctr{\jpgimage{20b}{526}{338}{40}}

\block{Figure 20B reprinted with permission, from: Green WR, Enger C.
Age-related macular degeneration histopathologic studies. The 1992
Lorenz E. Zimmerman Lecture. Ophthalmology 1993; 100:1519-35.}

\p{\panel{C}}

\ctr{\jpgimage{20c}{526}{338}{45}}

\block{Figure 20C reprinted with permission, from: Green WR, Enger C.
Age-related macular degeneration histopathologic studies. The 1992
Lorenz E. Zimmerman Lecture. Ophthalmology 1993; 100:1519-35.}

\p{\panel{D}}

\ctr{\jpgimage{20d}{526}{338}{42}}

\block{Figure 20D reprinted with permission, from: Green WR, Enger C.
Age-related macular degeneration histopathologic studies. The 1992
Lorenz E. Zimmerman Lecture. Ophthalmology 1993; 100:1519-35.}

}