Download Characterization of Retrokeratoprosthetic Membranes in the Boston

CLINICAL SCIENCES
Characterization of Retrokeratoprosthetic
Membranes in the Boston Type 1 Keratoprosthesis
Rebecca C. Stacy, MD, PhD; Frederick A. Jakobiec, MD, DSc; Norman A. Michaud, MS;
Claes H. Dohlman, MD, PhD; Kathryn A. Colby, MD, PhD
Objective: To evaluate retroprosthetic membranes that
can occur in 25% to 65% of patients with the Boston type
1 keratoprosthesis (KPro).
Methods: Two patients with Peter anomaly and 2 with
neurotrophic scarred corneas underwent revisions of their
type 1 KPros because of visually compromising retroprosthetic membranes. The excised membranes were studied
by light microscopy with hematoxylin-eosin, periodic acid–
Schiff, and toluidine blue stains. Immunohistochemical and
transmission electron microscopic examination were also
used.
Results: Light microscopic examination revealed that
the retro-KPro fibrous membranes originated from the
host’s corneal stroma. These mildly to moderately vascularized membranes grew through gaps in the Descemet membrane to reach behind the KPro back plate and
adhere to the anterior iris surface, which had undergone partial lysis. In 2 cases, the fibrous membranes
merged at the pupil with matrical portions of metaplastic lens epithelium, forming a bilayered structure that
crossed the optical axis. Retro-KPro membranes stained
positively for ␣–smooth muscle actin but negatively for
pancytokeratin. Electron microscopy confirmed the presence of actin filaments within myofibroblasts and small
surviving clusters of metaplastic lens epithelial cells.
Conclusions: Stromal downgrowth, rather than epithelial downgrowth, was the major element of the retroKPro membranes in this series. Metaplastic lens epithelium also contributed to opacification of the visual axis.
Florid membranous inflammation was not a prominent
finding and thus probably not a requisite stimulus for
membrane development. Further advances in prosthetic design and newer antifibroproliferative agents may
reduce membrane formation.
Arch Ophthalmol. 2011;129(3):310-316
T
Author Affiliations: David G.
Cogan Laboratory of
Ophthalmic Pathology
(Drs Stacy and Jakobiec), Howe
Laboratory (Mr Michaud), and
Cornea and Refractive Surgery
(Drs Dohlman and Colby),
Massachusetts Eye and Ear
Infirmary and Harvard Medical
School, Boston, Massachusetts.
HE BOSTON TYPE 1 KERATOprosthesis (KPro) has been
successfully used to restore
vision in cases of chronic
corneal disease and graft failure. This device, which consists of a clear
polymethyl methacrylate optic and back
plate (flange) with a titanium locking ring,
is implanted in a corneal graft that is then
transplanted into the patient’s eye.1 The back
plate is made of polymethyl methacrylate,
or more recently, titanium,2 and is perforated by holes to allow aqueous nourishment of the donor cornea. The back plate,
which is inserted into the patient’s cornea,
is slightly larger (by 0.5 mm) than the trephined punch in the patient’s eye. This design was intended to create a slightly overriding back plate for promoting a tight
junction between the host’s and donor’s
stroma at the wound site. The host corneal
tissue may swell at this interface, however,
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310
protruding slightly posteriorly into the anterior chamber (Figure 1A).
The clear optic provides excellent visual acuity, and the Boston KPro is
generally well retained.3-6 The postoperative development of retroprosthetic membranes is unfortunately relatively common, occurring in 25% to 65% of patients
within a year after KPro implantation. Up
to 45% of these cases require eventual
treatment.3-5,7 In most cases, the membrane can be cleared with YAG membranotomy, but approximately 11% require
surgical revision with explantation of the
KPro device and associated membranous
and corneal tissue.3 The histopathologic
features of such retro-KPro membranes
have previously received limited attention.8 In this series of 4 cases, we report
in greater detail the histopathological characteristics and origins of retro K-Pro
membranes from 4 explanted grafts, with
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A
B
∗
Donor cornea
∗
Host cornea
Descemet
membrane
Figure 1. The structure and anatomy of an in situ type 1 keratoprosthesis (KPro) and a retro-KPro membrane. A, The host cornea is slightly swollen at the edge of
the KPro back plate (which attaches circumferentially to the optic as a flange), resulting in an overhang of corneal tissue that protrudes into the anterior chamber.
The resulting gap in the Descemet membrane (*) permits migration of proliferating fibroblasts. B, A subtle retro-KPro membrane (arrow) obscures the visual axis
behind the clear optical center of the KPro. The holes in this titanium KPro back plate to facilitate nourishment of the overlying stroma are visible through the
donor cornea.
supplemental immunohistochemical and transmission
electron microscopic findings.
METHODS
Four explanted Boston type 1 KPros with attached retro-KPro
membranes were received by the David G. Cogan Laboratory
of Ophthalmic Pathology at the Massachusetts Eye and Ear Infirmary between September 2009 and April 2010. Each patient’s initial KPro surgery and the surgical revisions were performed at the same institution by 1 of 2 primary surgeons
(C.H.D. and K.A.C.), 1 of whom did 3 of the surgeries. During
the surgical revisions, the patient’s existing KPro was removed intact with its attached retroprosthetic membrane and
surrounding donor corneal tissue. This complex was placed in
formalin, and after a minimum of 48 hours, the donor cornea
and retroprosthetic membranes were dissected off of the polymethyl methacrylate or titanium KPro back plate. Under a grossing microscope, the donor cornea was bisected or trisected radially, and each piece was then peeled off the front surface of
the KPro. The back plate was then flipped over for continued
dissection of the retro-KPro membrane, which was peeled away,
while still attached to the corneal donor tissue at the edge. This
resulted in 2 or 3 U-shaped pieces of tissue per KPro, with 1
leg of the U formed by the donor cornea and the other by the
retro-KPro membrane. Care was maintained to preserve the connection between the donor cornea and fibrous membrane during dissection.
The tissue was further sectioned, embedded in paraffin, and
stained with hematoxylin-eosin. Immunohistochemical stains
for ␣–smooth muscle actin (SMA) (prediluted mouse monoclonal IgG; Ventana Medical Systems, Tucson, Arizona) and
pancytokeratin (mouse monoclonal IgG, 1:80 and 1:160; Becton Dickinson, San Jose, California, and Signet Laboratories,
Dedham, Massachusetts) were used following standard staining protocols9,10 on Ventana Benchmark automated immunostainers (Ventana Medical Systems) at the Massachusetts General Hospital. In 2 cases, some of the tissue that had been peeled
off of the back plate was submitted for transmission electron
microscopy after fixation in Karnovsky fixative (glutaraldehyde, 2.5%, and formaldehyde, 2%, in 0.1M cacodylate buffer
with 2.5mM calcium chloride). Tissue was processed through
aqueous osmium tetroxide, 2%, and graded ethanol, transitioned with propylene oxide, and embedded in an epon substitute (t-Epon; Tousimis Research Corporation, Rockville, Mary-
land). One-micron sections were stained with toluidine blue
and 70-nm-thin sections were stained with saturated uranyl acetate and Sato lead stain. Sections were examined with transmission electron microscopy (Philips CM 10; Philips Scientifics, Eindhoven, the Netherlands).
RESULTS
CLINICAL CHARACTERISTICS
Four patients with scarred and opacified corneas due to
Peter anomaly (2 cases) or neurotrophic corneas (2 cases)
received Boston type 1 KPros. Preoperative objective studies of trigeminal nerve dysfunction were not performed
in the patients with Peter anomaly who had already had
failed corneal transplants. In all patients, the diameter
of the back plates was 8.5 mm, except for a 2-year-old
who received a 7.0-mm back plate. Two patients had several failed penetrating keratoplasties before receiving the
KPro, and 1 patient had a failed corneal patch graft. Further clinical characteristics of all 4 cases are summarized in the Table.
Three patients developed clinically evident retroKPro membranes between 3 and 4 months after surgery
(Figure 1B). Patient 1 displayed a retro-KPro membrane 3 months after her initial KPro placement. YAG
capsulotomy (40 pulses at 2.8 mJ) failed to break through
the retroprosthetic membrane; surgical excision was then
performed. In patient 2, a retro-KPro membrane was observed 4 months after the initial KPro implant. YAG capsulotomy (18 pulses at 3 mJ) was attempted at 7 months
postoperatively and was initially successful, but regrowth of the membrane within 6 weeks required surgical revision. Patient 3 was a 2-year-old child who developed a retro-KPro membrane 4 months after her initial
surgery. At 5 months, she developed the additional complication of a partial KPro extrusion and proceeded to
surgery without YAG treatment. Patient 4 had a KPro that
was scheduled for surgical revision because of a descemetocele. A retro-KPro membrane had not been observed prior to surgery, but during the surgical repair and
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Table. Clinical Characteristics of Patients With KPro
Patient
No./Sex/ Indication for
Age, y
Original KPro
Other Ocular
Diagnoses
Previous
Failed
Corneal
Surgeries
Pseudophakia, PK ⫻4
glaucoma
1/F/27
Peter anomaly
2/M/57
Neurotropic,
Pseudophakia, No prior
vascularized
retinal tear
corneal
⫻2,
surgery
cornea with
scar after
hypotony
decompensation OD,
with silicone
after
vitrectomy
oil
Peter anomaly
Glaucoma
PK ⫻2
3/F/2
4/F/74
Neurotrophic
cornea after
graft needing
valve for IOP
control
Ruptured
globe 5 y
prior,
glaucoma,
herpes
simplex
Patch graft
for corneal
perforation
Preop VA
Before Any
KPro
Time Before
Membrane
Seen/
Removed, Supplementary
mo
YAG
CF 2 ft
3/4
CF 1 ft
4/10
VA Before
KPro
Explantation
Original
KPro Back
Final VA
Plate
(Time After
Diameter,
Second KPro,
mm; Material
mo)
3 mo: 40
CF 2 ft
8.5; Titanium
pulses
at 2.8 mJ,
failed
20/400
8.5; PMMA
7 mo:18
pulses
at 3 mJ but
then
recurred
after
6 wk
No
Roving eye
7.0; Titanium
movements
Roving eye
4/5
movements
(toddler)
No
HM
Not seen
clinically,
discovered
when
descemetocele
repaired at
5 mo
20/70
8.5; Titanium
20/100 (4);
No
membrane
seen
20/200 (2);
Trace
membrane
Not noted
(child)
(1 d)
HM (2.5);
developed
hypotony,
sterile
vitritis,
choroidal
effusions,
no
membrane
Abbreviations: CF, count fingers; HM, hand motions; IOP, intraocular pressure: KPro, keratoprosthesis; OD, right eye; PK, penetrating keratoplasty;
PMMA, polymethyl methacrylate; Preop, preoperative; VA, visual acuity.
on gross examination, a delicate membrane was detected. All patients received a second KPro except for patient 3, who underwent a revision with a penetrating keratoplasty because of thinning at the surgical site and the
primary need for tectonic stability.
LIGHT MICROSCOPIC,
ELECTRON MICROSCOPIC, AND
IMMUNOHISTOCHEMICAL FINDINGS
All cases were first examined and dissected under the
grossing microscope, which revealed a fibrous membrane that emanated from the edges of the donor cornea
on the anterior surface of the KPro. This membrane had
an omnidirectional growth pattern in the anterior chamber, in addition to wrapping around the edge of the back
plate and extending along its posterior surface to obscure the optical axis. Possible growth through holes in
the retrocorneal titanium plate could not be evaluated
because this material could not be sectioned. The membrane was composed of an inner layer of opaque fibrous
tissue and an outer pigmented layer. In all cases, the fibrous membranes were found to be adherent to the back
plate and required gentle, persistent traction to peel away,
suggesting indirectly some growth and protrusion of the
membrane within the holes in the back plate.
In 2 cases, the connections between the retro-KPro
membrane and the donor cornea were well preserved after processing and staining of the tissue. On low-power
microscopy, the gap left by the KPro back plate between
the donor cornea and retro-KPro membrane was evident (Figure 2A). The retro-KPro membrane was com-
posed of 3 layers: a corneal stromal fibrous membrane,
the iris stroma and pigmented posterior neuroectoderm, and metaplastic lens epithelium and elements of
its persistent capsule. Evaluation of the healed wound
interface between the host and donor cornea (Figure 2B)
demonstrated that the fibrous retro-KPro membrane originated from the hypercellular host side and not the quiescent hypocellular donor aspect of the wound. Surface
epithelial invasion of the wound, even partway, was not
discovered. Adjacent sections disclosed gaps in the Descemet membrane; fragments of it had been displaced and
swept along by the invading fibrous tissue (Figure 2C).
The fibrous membrane adhered to, but did not invade, the friable and dissolving pigmented iris stroma.
Despite the segmental disappearance of the stroma, the
iris sphincter muscle was variably preserved (Figure 2D).
The posterior pigmented neuroectodermal epithelium was
observed to be displaced toward the pupil by traction
(Figure 2E). The fibrous membrane extended toward the
chamber angle as well as toward the pupil, where it merged
with the metaplastic lens epithelium, capsular remnants, and its associated extracellular matrix (Figure 2D
and E) to obscure the pupillary axis. New basement membranes that were brilliantly periodic acid–Schiff positive
were generated by the metaplastic lens epithelium; they
also contributed to the retro-KPro membrane in the pupillary zone (Figure 2D and E). The portion of the fibrous membrane that extended toward the chamber angle
adhered to, and produced wrinkling of, the Descemet
membrane (Figure 2E, inset).
In 1 of the cases of a neurotrophic cornea (patient 2),
moderate vascularization of the stromal membrane and
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A
B
D
D
H
1
2
FM
3
C
D
FM
S
∗
E
C
F
H
FM
FM
FM
NE
L
Figure 2. Histopathologic and immunohistochemical features of retrokeratoprosthesis (retro-KPro) membranes. A, The donor cornea (D) above and the fibrous
membrane (1) below delimit the empty space occupied by the back plate of the KPro (double-headed arrow). In addition to the fibrous downgrowth (1) from the corneal
stroma making a “U” on the left (arrow), also seen are the disrupted iris (2) and the metaplastic lens epithelium with its capsule (3). B, Higher magnification of the
host-graft junction (arrow) discloses origination of the fibrous membrane (FM) from the hypercellular stroma of the host’s cornea (H). The donor (D) corneal tissue at
the interface is sharp and paucicellular. C, In adjacent sections, fragments of the Descemet membrane (arrows) have been displaced and trapped within the stromal
downgrowth as it wraps around the KPro back plate to abut the underlying iris (*). D, Periodic acid–Schiff stain demonstrates growth of the fibrous membrane (FM)
above the iris sphincter muscle (S) to merge on the right with the metaplastic lens epithelium and capsular remnants. The iris stroma has completely atrophied and been
replaced by a thin scar. The thicker native lens capsule (arrows) contrasts with the thinner new basement membrane (crossed arrow) that has formed around clusters of
metaplastic lens epithelial cells. E, Periodic acid–Schiff stain highlights the fibrous retro-KPro membrane (FM), displaying moderate vascularization (arrows). A remnant
of the iris sphincter is seen within the iris stroma (crossed arrow). The lens capsule with metaplastic lens epithelium (L) lies posterior to the iris. The pupillary region
(toward the bottom, right) has been plugged by a combination of the fibrous membrane, displaced posterior neuroectodermal iris pigmented epithelium (NE), and
metaplastic lens epithelial membrane (L). Inset: In peripheral regions, the fibrous membrane (FM) adheres to the Descemet membrane (arrow) and through contraction
pulls it away from the host cornea (H) to cause undulations. F, Top panel: The retro-KPro fibrous membrane (FM) is positive for smooth muscle actin. Note smooth
muscle actin positivity in the deep corneal stroma (C) above the Descemet membrane (arrows). Bottom panel: The retro-KPro membrane is negative for pancytokeratin.
(A-C, toluidine blue, original magnification ⫻25, ⫻100, and ⫻100, respectively; D, E, and E inset, periodic acid–Schiff, original magnification ⫻25; F top and bottom,
immunoperoxidase reaction, original magnification ⫻100.)
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A
P
N
R
R
2.0 µm, ×10 500
B
LE
C
R
R
5 µm, ×4600
there was an inflammatory response evidencing a plethora
of neutrophils. Immunostaining with SMA in this membrane also revealed many myofibroblasts and nonpancytokeratin-staining cells. Actin positivity was also observed in surviving metaplastic lens epithelial cells in the
2 specimens displaying this feature.
Electron microscopy of the retro-KPro fibrous membrane from a patient with Peter anomaly revealed an abundance of elongated myofibroblasts (Figure 3A). These
cells had dichotomously branching rough endoplasmic
reticulum and scattered thin (actin-type) subplasmalemmal cytoplasmic filaments with fusiform densities but betrayed no basement membrane formation. The extracellular space separating these cells was uniformly composed
of collagen fibers. Examination of the most posterior layer
of the membrane showed small, rounded lens epithelial
cell groupings adjacent to the lens capsule (Figure 3B).
Thin actin cytoplasmic filaments were also discerned in
these cells along with abundant parallel profiles of rough
surface endoplasmic reticulum. The cells were insulated from the matrix by surrounding, relatively prominent basement membranes that were not synthesized
where adjacent epithelial cell membranes approximated each other (Figure 3B, inset). The extracellular matrix enveloping these cell clusters was amorphous, granular, and fibrillar and contained cellular detritus.
M
COMMENT
5 µm, ×2600
Figure 3. Transmission electron microscopy of the fibrous
retrokeratoprosthesis (retro-KPro) membrane. A, Electron micrograph of the
retro-KPro fibrous membrane demonstrates an elongated resident fibroblast
without a basement membrane. It is endowed with abundant rough
endoplasmic reticulum (R) and contains cytoplasmic subplasmalemmal
filaments (arrow) with fusiform densities (crossed arrow). A delicate fibroblast
cell process (P) is seen nearby. N indicates nucleus. B, Electron micrograph of a
portion of the retro-KPro membrane composed of the lens epithelial cells (LE)
found adjacent to the thick native lens capsule (C). The cells contain myriad
parallel profiles of rough endoplasmic reticulum (R) and display
subplasmalemmal thin actin-type filaments (crossed arrows in main panel and
inset). The cells are surrounded by a prominent basement membrane (arrows).
M indicates extracellular fibrillogranular matrix containing degenerated cell
remnants. (A, electron micrograph, original magnification ⫻10 500; B and inset,
electron micrograph, ⫻2600 and ⫻4600.)
the iris surface was observed (Figure 2E). Vascularization of the retroprosthetic fibrous membrane emanated
from the host’s, not the donor, corneal stroma. The fibrous component of the retro-KPro membranes of all 4
specimens stained positively for SMA (Figure 2F, top
panel), with positive vessel walls serving as internal controls. The deep pre-Descemet keratocytes also expressed SMA (Figure 2F, top panel). Pancytokeratin staining, which immunoreacts with surface squamous
epithelium and corneal metaplastic endothelium,11 was
negative in the membrane (Figure 2F, bottom panel). The
amount of intramembranous inflammation in our cases
varied. Two retro-KPro membranes did not evince any
significant inflammation. One patient with Peter anomaly
(patient 1) had focal infiltrates of chronic inflammatory
cells unrelated to vascularization. Finally, 1 patient with
a neurotrophic scarred cornea and a descemetocele (patient 4) displayed a retro-KPro membrane with myxoid
cellularity and a loosely woven collagenous appearance;
The development of a retro-KPro membrane can be a
sight-limiting complication to an otherwise successful solution for managing refractory corneal opacification. Even
in initially successful YAG membranotomies, recurrence is possible because there is no deterrent to ongoing robust fibroplasia. These were the situations in 2 of
our cases, which were among the most severe membranes encountered in our study. We have demonstrated that retro-KPro membranes, specifically those that
are dense enough to resist YAG membranotomy, can be
composed of multiple layers that include (1) a compact
fibrous membrane behind the back plate consisting of stromal downgrowth from the host’s cornea; (2) the patient’s native iris stroma in varying states of preservation, which tightly adheres to the posterior surface of the
membrane; and (3) a retroiridial membrane stemming
from the metaplastic lens epithelium that synthesizes the
matrix and merges with the anterior chamber retrocorneal fibrous membrane at the pupil to becloud it. In patient 4, who had an antecedent corneal perforation and
a later descemetocele, the retro-KPro fibrous membrane
was relatively thin and myxoid with an acute inflammatory reaction. This membrane had not been observed clinically (acuity was 20/70 at the time of explantation) and
was only encountered on gross examination of the explanted KPro. In all other cases, the fibrous membranes
were well collagenized, with minimally inflamed matrices that included mild vascularization originating from
the host’s side of the wounded corneal stroma. The composition of the retro-KPro membrane may therefore vary,
depending on antecedent clinical events. In the more recalcitrant membranes, the dense tissue had fused with
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the anterior border layer of the iris stroma to cause the
latter’s distortion, dissolution, and focal necrosis but did
not invade it. Care must therefore be taken to remove
all membranous components during excisions to clear
the pupillary obstruction.
Another earlier report of explanted Boston KPros described 4 fibrous membranes with epithelial migration
partway into the wound,8 which was not observed in our
case material. Different clinical features may help to explain the disparate incidences of epithelial downgrowth
reported in the earlier and present studies. Autoimmune or inflammatory disease, which was present in 3
of the 4 previous patients with reported epithelial downgrowth, can promote intense vascularization of the retrocorneal stromal membrane that in turn can lend support to an epithelial downgrowth.12-16 Therefore, both
stromal and epithelial anterior chamber invasion can develop together. None of our patients had systemic or local inflammatory conditions but were instead treated for
developmental abnormalities or neurotrophic scarred corneas. The latter condition is known to be associated with
defective corneal wound healing, which could be conducive to fibrous ingrowth around a prosthesis.
In our opinion, another factor (besides inflammation) more likely contributes to membrane formation.
Breaks in the Descemet membrane and displacement of
Descemet fragments seen in our samples support the view
that they allowed a pathway for migration of the host
stroma into the anterior chamber. In our series, stromal
downgrowth was only observed at these sites; furthermore, stromal cellularity was much more prominent on
the host’s side of the corneal wound than on the donor’s
side. As the host stroma swells, it can override the lateral border of the KPro back plate, and the fibrous ingrowth may then proliferate around this edge to cover
the posterior aspect of the back plate. Myofibroblasts have
been shown to arise from differentiated stromal keratocytes that are stimulated following corneal wound formation.17,18 The breaks in the Descemet membrane during the KPro surgery may trigger mechanisms for the
ingrowth of myofibroblasts and the synthesis of extracellular membranous components, such as collagen and
glycosaminoglycans.18-23
The specimens in our series stained negatively for pancytokeratin, a marker that is identified in retrocorneal
membranes derived from epithelial downgrowth.11,24 Various cytokeratins can also be expressed along with SMA
in damaged or metaplastic endothelial cells,11,25 but this
cellular source for our membranes was ruled out by negative immunohistochemical staining for keratin. Similar
results establishing a stromal source have been obtained in studies of retrocorneal membranes following
penetrating keratoplasties.13,18,19,22 The presence of stromal myofibroblasts in our cases was confirmed by electron microscopy in accord with prior studies.17,18 The myofibroblasts displayed sufficient contractility to produce
wrinkling of the Descemet membrane and displacement
of its fragments,11 as shown in 2 of our specimens. The
second component of our patients’ membranes was the
coparticipation of remnants of lens capsule and epithelium. The epithelium underwent metaplasia and elaborated an extracellular collagenous matrix while still pre-
serving ultrastructural features of an epithelium with the
acquisition of thin cytoplasmic actin filaments. Patients
1 and 2 were pseudophakic before their initial KPro surgery (Table); it is possible but unprovable that the lens
epithelium that comingled in membrane formation at the
pupil had already begun to undergo metaplasia before
the introduction of the KPro.
Close approximation of the stromal wound is also a
requirement to deter the fibrous downgrowth seen in the
formation of retro-KPro membranes. The possibility of
an unusually thick host peripheral cornea in the 2 patients with Peter anomaly leading to wound misalignment is intriguing but was not explored with preoperative anterior segment ultrasonography. A general redesign
of the back plate (flange) so that it is 9.5 mm in diameter (1.0 mm greater than the current design) could conceivably clamp the corneal wound to a more marked degree, thereby creating a more effective barrier to stromal
invasion. However, it would not completely abort the
wound response, which stimulates migrating myofibroblasts. Other interventions requiring in-depth evaluation that may decrease retro-KPro membrane formation
should focus on antiangiogenesis and antifibroplastic
agents. Bevacizumab and its analogs may not be helpful
in the context of stromal fibrous membranes if there is a
paucity of neovascularization but may withhold support for epithelial and/or fibrous downgrowth and impede membrane formation in the subset of patients with
ocular inflammatory conditions.
Because of the rarity and random character of tissue
availability represented, this study has 2 important limitations. While the surgeries were performed at the same
institution, the participation of 2 different primary surgeons introduced an uncontrolled variable in surgical technique. The inclusion in this study of only 2 clinical entities furthermore does not reflect the full range of possible
pathologic reactions, a subject that deserves further investigation as more varied tissues become available.
Submitted for Publication: May 20, 2010; final revision
received July 24, 2010; accepted July 28, 2010.
Correspondence: Frederick A. Jakobiec, MD, DSc, Massachusetts Eye and Ear Infirmary, 243 Charles St, Ste 321,
Boston, MA 02114 ([email protected]).
Financial Disclosure: None reported.
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