Pseudophakic Bullous

Keratopathy
Relationship to Preoperative Corneal
Endothelial Status
GULLAPALLI N. RAO, MD, JAMES V. AQUA VELLA, MD,
STUART H. GOLDBERG, MD, STEVEN L. BERK, MD

Abstract: Pseudophakic bullous keratopathy is one of the complications of

intraocular lens implantation. A knowledge of the preoperative status of
corneal endothelium may help to minimize the incidence of this complication.
The preoperative corneal endothelial status of 118 eyes of 102 patients who
received Worst-Medallion intraocular lenses more than five years ago was
analyzed retrospectively. This data was then correlated with the postoperative
clinical status of the cornea. Twelve eyes (10%) underwent penetrating
keratoplasty for irreversible corneal edema, and 28 of the remaining eyes
(22%) had clinical evidence of peripheral corneal edema. No correlation was
found between the preoperative endothelial cell density or the degree of
postoperative cell loss and the development of corneal edema. Significant
correlation was found between variation in cell size (pleomorphism) and the
development of postoperative corneal edema. Greater density of precipitates
on endothelium and abnormality in cell shape postoperatively were also
frequently seen in corneas that developed edema subsequently. [Key words:
cornea, coroeal edema, corneal endothelium, intraocular lens, pseudophakia,
pseudophakic bullous keratopathy.] Ophthalmology 91: 1135-1140, 1984

Pseudophakic bullous keratopathy is a serious com-
plication of intraocular lens implantation which consti-
tutes one of the most common indications for penetrating
keratoplasty in major corneal centers across the United
States. It has been conclusively demonstrated that intra-
ocular lens implantation can result in a considerable
degree of corneal endothelial cell damage, which may
be responsible for the development of corneal edema.
Early studies l have attributed this to mechanical trauma
From the Comea Research Laboratory and the Department of Ophthal-
mology, University of Rochester Medical Center, Rochester, New York.
Presented at the Eightyeighth Annual Meeting of the American Academy
of Ophthalmology, Chicago, Illinois, October 30-November 3, 1983.
Supported in part by grants from Bausch and Lomb Company.
Reprint requests to Gullapalli N. Rao, MD, 919 Westfall Road, Rochester,
NY 146182699.
during surgery. More recently, long-term follow-up has
revealed the existence of progressive changes in corneal
endothelium following intraocular lens insertion. 2,3 The
pathogenesis of this phenomenon is not clear, although
persistent low grade inflammation and intermittent con-
tact of the implant with the corneal endothelium are
considered probable causative mechanisms. The intro-
duction of posterior chamber lenses, improved design
and quality control of lenses, use of sodium hyaluronate
during surgery and better training of surgeons have all
contributed to a decline in corneal complications, at
least in the first few years after this procedure.
Despite these advances, corneal complications con-
tinue to be a concern following intraocular lens implan-
tation. In order to minimize their occurrence, an in-
creasing number of ophthalmic surgeons are subjecting
their patients to preoperative, clinical specular micros-
copy to obtain information concerning the morphologic

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 OPHTHALMOLOGY OCTOBER 1984
status of corneal endothelium. The significance of those
morphologic characteristics of endothelium as a predictor
of corneal reaction to surgery remains unknown. Most
clinicians use endothelial cell density as the single par-
ameter for evaluating the corneal endothelium. Evidence
thus far, however, has failed to demonstrate any signif-
icant relationship, between endothelial cell density and
corneal function. ,2 In an earlier report,4 we suggested
that the degree of variation in cell size may be a critical
parameter of endothelial cell morphology. Endothelium
showing a greater degree of variation (polymegathism)
was shown to react more adversely to intraocular surgery
manifested by a greater increase in corneal thickness
following surgery and a slower rate of deturgesence to
preoperative levels.
Identification of preoperative indices of endothelial
cell morphology which may determine the corneal re-
action to intraocular surgery is of great significance. In
order to address this question, we have studied the
corneal reaction of a group of patients who have had
intraocular lens implantation and correlated it with their
preoperative corneal endothelial cell morphology. The
development of corneal edema was used as a functional
marker in these eyes.
MATERIALS AND METHODS
PATIENT SELECTION
A total of 118 consecutive eyes of 102 patients who
had intraocular lens (IOL) implantation were included
in this study. The age of the patients ranged from 51 to
86 years (mean, 65.8 years). All patients had Worst-
Medallion intraocular lenses (iris suture type) implanted
at least five years prior to the analysis of these data with
a range of 62 months to 85 months and a mean of 71
months. Patients with evidence of preoperative anterior
segment pathology, intraoperative and related postop-
erative complications were excluded. Only those cases
where the surgery was uneventful were included in this
study. All procedures were performed by the same
surgeon (JV A), who had performed over 200 similar
operations prior to those involving patients in this study.
PREOPERATIVE EVALUATION
Preoperative evaluation consisted of detailed ophthal-
mological examination, pachymetry and measurement
of intraocular pressure using a Langham-type tonometer.
In addition, clinical specular microscopy was performed
preoperatively as well as postoperatively in all patients.
Cases with slit-lamp evidence of endothelial cell pathol-
ogy were excluded from IOL implantation.
SURGICAL TECHNIQUE
All surgery was performed with neurolept anesthesia
using a modified Van Lint procedure and retrobulbar
block using a combination of 2% lidocaine and 0 .75%
bipuvacaine. Following retrobulbar injection, digital
1136
VOLUME 91 NUMBER 10
massage was administered for a period of at least ten
minutes, and all patients received an intravenous injec-
tion of 20% mannitol. The total volume of mannitol
ranged from 100 to 300 ml to obtain a soft eye prior to
surgery. The remaining details of the surgical procedure
have been described previously.2
As Healon was not available, the IOLs were inserted
under a large air bubble.
CLINICAL SPECULAR MICROSCOPY
Procedure. All eyes were subjected to detailed clinical
specular microscopic evaluation using a Syber instru-
ment, preoperatively and postoperatively. A Nikon cam-
era attached to the specular microscope was used and
photographs were taken using Kodak Tri-X 400 film.
In each examination, at least ten photographs were
taken of the central corneal endothelium. The photo-
graphs were then subjected to a specialized photographic
process to enhance the quality of the cell outlines. Three
endothelial photographs were selected from each of these
eyes on the basis of the quality of details. Overlays were
then made and subjected to automated image analysis.
Analysis of specular photomicrographs. The specular
photomicrographs were analyzed both qualitatively and
quantitatively. Qualitative analysis was accomplished by
examining the negatives under high magnification in
good illumination. Observations included abnormal cell
morphology, presence of precipitates and guttata. These
changes were then graded from trace to 4+ depending
on severity. Quantitative analysis was performed using
a previously described automated image analysis system. 5
This included determination of mean cell density, mean
cell area and coefficient of variation in cell area. This
latter index provides information on the variation in
cell size in the studied endothelium (one of the features
of pleomorphism).
OTHER EVALUATION
Central corneal thickness was measured in all cases,
both prior to IOL implantation and in the postoperative
period, using a Haag-Streit pachymeter incorporating
the Mishima-Hedbys modification. Intraocular pressure
was also measured on each visit using a Langham-type
pneumotonometer.
Statistical analysis was performed on all the cases.
Mean endothelial cell density (ECD) and standard de-
viation were determined. In addition, the percentage of
postoperative cell loss was calculated. A two-sample t-
test was used to determine any differences between
groups of patients.
Specular microscopy, surgical procedure, data analysis
and statistical analysis were performed by different in-
vestigators.
RESULTS
Of the 118 eyes included in this study, penetrating
keratoplasty was required in 12 eyes for irreversible
 RAO, et al PSEUDOPHAKIC BULLOUS KERATOPATHY

Table 1. Endothelial Cell Density (Cells/mm 2) Table 2. Relationship Between Cell Loss and Corneal Decompensation

Group 1* Group 2t Cell Number Decompensated After:

Loss
Mean preoperative cell density 2838 2813 (%) 1 yr. 2 yr. 3 yr. 4 yr. 5 yr.
(range) (1748-4262) (1842-3864)
Mean cell loss (%) 42.12 43.02 10 None
20 1 1 4
* 78 patients; clear cornea. t40 patients; corneal edema. 30 1 2 4
40 3 2 2 3
corneal edema following intraocular lens implantation. 50 2 4 3
Edema developed peripherally and subsequently became 60 1 1 3
diffuse in eight cases, and il1 four cases was diffuse from
the onset. The time interval between intraocular lens
implantation and subsequent penetrating keratoplasty cell size. In Group 1 (clear cornea), this value ranged
ranged from 1.6 to 4.3 years (mean, 2.9 years). There from 17.2 to 41.2 (mean, 27.4), and in Group 2 (corneal
were no detectable intraoperative or postoperative com- edema), the range was from 18.8 to 52.4 (mean, 40.7).
plications in these 12 eyes. The difference between the two groups is statistically
Twenty-eight of the remaining eyes presented clinical very significant (P > 0.0001) using two-sample t-test
evidence of corneal edema at the time of the last (Table 3). Figure 1 represents corneal endothelium with
examination. Edema was confined to the peripheral relative uniformity in cell size, while Figure 2 shows
parts of the cornea sparing the central cornea, facilitating marked degree of variation in cell size.
the preservation of good visual acuity. Edema started Qualitative analysis did not demonstrate any signifi-
superiorly in 20 of these eyes, inferiorly in six, and cant abnormalities in the preoperative endothelial pho-
nasally in two. There was no evidence of any other tomicrographs. 111 the postoperative period, however,
complication that might have led to corneal edema. 10 1 of the 118 corneas demonstrated some degree of
There was an increase in stromal thickness in the areas precipitates on endothelium. When these changes were
associated with epithelial edema. graded, 18 of the 78 eyes (25.4%) in Group 1 demon-
The remaining 78 eyes had no clinical evidence of strated changes greater than grade 2, while 22 of the 40
corneal pathology excepting for the presence of precipi- eyes (55.0%) in Group 2 demonstrated such changes,
tates 011 corneal endothelium. pointing to a greater incidence of el1dothelial precipitates
A retrospective analysis of the data obtained from the in Group 2 (Fig 3). Guttata-like changes characterized
endothelial cell morphology studies was conducted, For by dark, acellular areas were found in 11 eyes of Group
this analysis, the 78 eyes that maintained clear corneas 1 (14.2%) and 8 eyes (20.0%) of Group 2 (Table 4).
were considered as Group 1. The remaining 40 eyes Close scrutiny of postoperative endothelial cell mor-
which had clinical corneal edema (12 requiring pene- phology demol1strated inarked irregularity in cell shape
trating keratoplasty and 28 with peripheral corneal with a l1umber of cells attaining abnormal shapes losing
edema) were classified as Group 2. the normal polygonal appearance (Fig 4). These obser-
Preoperative endothelial cell density in Group.l ranged vations were only qualitative. Such changes were noted
from 1748 to 4262 cells/mm2 (mean, 2838). The corre- in 15 eyes of Group 1 (19.4%) and in 9 eyes of Group
sponding figures for Group 2 ranged from 1842 to 3864 2 (47.5%) suggesting a difference between the two groups
cells/mm2 (mean, 2813). The difference between the two (Table 3).
groups was not statistically significant (two-sample t- Central corneal thickness measurements did not dem-
test) (Table 1). onstrate any significant difference between the two
Postoperative cell loss was determined by using the groups, either preoperatively, or before any evidence of
value of endothelial cell density from the last specular edema manifested postoperatively.
microscopic examination. For the 12 eyes that developed
diffuse corneal edema, precluding specular microscopy,
the figures from the examination prior to the develop- DISCUSSION
ment of edema were considered. The mean percentage
cell loss was 42.12 for Group 1 and 43.02 for Group 2 In the present study, we have attempted to identify
(Table 1) with no significant difference between the two morphological parameters of corneal endothelium that
groups (two-sample t-test). The degree of postoperative
cell loss and the length of the postoperative period did Table 3. Coefficient of Preoperative Variation in Cell Area
not show any correla.tion with the development of
corneal edema (Table 2). Group 1* Group 2t
Preoperative coefficient of variation in cell area was
then considered for analysis. This value provides an 27.4 40.7
Mean value (range) (17.2-41.2) (18.8-52.4)
index of the variation of cell size in endothelium. The
(P< 0.00001)
closer this value to zero, the more uniform the cell size;
the closer the value to 100, the greater the variation in * 78 patients; clear cornea. t40 patients; corneal edema.

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 OPHTHALMOLOGY OCTOBER 1984 VOLUME 91 NUMBER 10

Fig 1. Left. specular photomicrograph showing corneal endothelium in a 71-year-old man. Cell density, 2866 cells/mm2 ; Coefficient variation,
28.4. The endothelium is relatively uniform in cell size. Right. overlay of the endothelial photograph in Figure I, demonstrating relative uniformity
in cell size.

may help to predict the reaction of cornea to surgical
trauma. We have studied patients who underwent the
same surgical procedure performed by the same surgeon,
experienced with the techniques used.
The present series represents a fairly high incidence
()f pseudophakic bullous keratopathy following implan-
tation with Worst-Medallion-type IOL. Of the 118 eyes
that were included, 12 eyes (10%) already had penetrating
keratoplasty for corneal edema. Of the remaining eyes,
28 eyes (22%) had clinical evidence of peripheral corneal
edema. Good visual acuity was preserved in the latter
group of patients because of the clear central area of the
cornea. However, from our observations on the patients
who have demonstrated progression of edema, this phe-
nomenon may eventually involve the entire cornea
producing a visual deficit. The possibility of such a
development will increase the incidence of corneal edema
in our series to alarmingly high figures.
The phenomenon of progression of corneal edema
can perhaps be explained by the available evidence on
the endothelial cell damage that occurs following intra-
ocular surgery.6 Cataract surgery produces a greater
degree of cell damage in the superior part of the cornea
where the incision is made. The occurrence of edema
in the superior part of the cornea is most likely a
reflection of this phenomenon. Development ()f edema
in the inferior cornea may be due to the contact of the
implant with the endothelium in this area during surgery,
as well as to intermittent contact of the implant with
the endothelium following surgery.
From the clinical data on these patients, no definite
factor could be identified that may be incriminated in
the causation of corneal edema. This does not, however,
eliminate the possibility of recurrent episodes of "inter-
mittent touch" of the lens with the corneal endothelium.
If such a phenomenon were to be responsible for the
development of corneal decompensation, one would
expect the same phenomenon to occur in all the eyes.
One can explain the discrepancy in the ultimate corneal
status between the two groups only on the basis of a
possible difference in the functional reserve of the corneal
end()thelium.
Endothelial status prior to IOL implantation was
correlated with the clinical course in these corneas
following the implantation in order to address this
question.
Cell density is the most common quantitative param-
eter used for the preoperative and postoperative evalu-

Fig 2. Left. corneal endothelium of a 68-year-old man, demonstrating marked variation in cell size. Cell density, 2922 cells/mm2; Coefficient
variation, 48.2. Note the areas of large cells surrounded by small cells. Right. overlay of the specular photograph in Figure 2, highlighting the
marked variation in cell size. }
;
~
,i
1138 1
,:i
 RAO. et al PSEUDOPHAKIC BULLOUS KERATOPATHY
Fig 3. Endothelium of a 68-year-old man, demonstrating marked
degree of precipitates on the endothelium four and one,half years
following intraocular lens implantation using a Worst-Medallion lens.
Cell density, 842 cells/mm2.
ation of corneal endothelium. No significant difference
existed in the preoperative mean endothelial cell density
between those eyes which ultimately developed corneal
edema following IOL implantation and those which
maintained clinically clear corneas. Similarly, no signif-
icant difference was seen in the percentage of postoper-
ative cell loss between the two groups. Thus, endothelial
cell density in the range seen in this study did not
appear to be a major determinant of the fate of corneas
subjected to surgical trauma.
The coefficient of variation in cell area was examined.
The value is an index of the variation in cell size which
represents one of the facets of cellular pleomorphism.
Analysis of these data demonstrated that the mean
values between the two groups differed significantly with
the group that developed corneal edema demonstrating
an obviously greater degree of variation in cell size.
From this, it appears that corneas with greater degree of
variation in cell size (polymegethism) are more vulnerable
to surgical trauma and have less functional reserve. This
observation confirms our earlier observations on IOL
patients;4 this morphological parameter deserves close
scrutiny as a predictor of endothelial functional reserve.
Gross examination of corneal endothelial photographs
with a higher coefficient of variation in cell size show
considerable difference in size between the smallest and
the largest cell in the same field. Other presentations are
a rosette-like pattern with small cells surrounding a large
cell, or islands of large cells scattered among very small
cells.
Normal corneal transparency is maintained by an
intact barrier function of endothelium and the activity
of the metabolic pump. Following surgical trauma, there
is disruption of these mechanisms resulting in some
degree of corneal edema. A rapid return to the normal
state is a reflection of rapid reestablishment of both
these processes. However, if this return to normalcy is
delayed, one has to postulate that one or both these
functions are compromised in the endothelium of that
given cornea. Marked variation in cell size represents
an aberration in cell morphology. Such an aberration
may result in diminished functional ability. Large cells
Table 4. Qualitative Postoperative Changes
Group 1* Group 2t
Precipitates (greater than 2+) 18 (25.4%) 22 (55%)
Guttata-like changes 11 (14.2%) 8 (20%)
Abnormal cell morphology 15 (19.4%) 19 (47.5%)
* 78 patients; clear cornea. t40 patients; corneal edema.
seen in these corneas may not interdigitate well with
small cells, leading to an ineffective structural barrier of
endothelium, leading to a diminution in the functional
competence of this layer, and resulting in a compromise
of endothelial function and corneal edema.
A similar phenomenon was noted on examination of
the postoperative endothelial cell morphology. Patients
who developed corneal edema demonstrated marked
abnormality in cell shape in a greater number of eyes,
when compared to those patients who maintained clear
corneas.
In some eyes, chronic low-grade inflammation may
have been responsible for the ultimate demise of the
cornea. This is evidenced by the increase in the incidence
of corneal edema in eyes which demonstrated moderate
to severe degree of precipitation on the endothelium.
The quantity of precipitates may be an index of the
degree of chronicity of inflammation. Both inflammation
and precipitates may lead to a diminution in endothelial
function which, in tum, leads to corneal decompensation.
Close follow-up of patients demonstrating these changes
is warranted to prevent irreversible changes. The effect
of precipitation or inflammation may be more deleterious
to the endothelial layer, with marked abnormality of
cell shape.
This study suggests that marked variation in endothe-
lial cell morphology represents an aberrant endothelium
which is functionally less competent. Greater attention
must be devoted to this feature in the analysis of
specular photomicrographs in patients where major in-
traocular surgical intervention is contemplated. This
Fig 4. Corneal endothelium demonstrating abnormalities in cell shape
in a 70-year-old man, three and one-half years following intraocular
lens implantation with a Worst-Medallion lens. Cell density, 840 cells/
mm2 Note the absence of the regular polygonal appearance of the
corneal endothelium.
1139
 OPHTHALMOLOGY OCTOBER 1984
information may also have application in the assessment
of donor corneas prior to corneal transplantation.
ACKNOWLEDGMENTS
Alex Martens of Bausch and Lomb Company provided
assistance with image analysis. Gangaji Maguluri of the De-
partment of Statistics at the University of Rochester provided
the statistical analylsis.
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VOLUME 91 NUMBER 10
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