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

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OPHTHALMOLOGY OCTOBER 1984 VOLUME 91 NUMBER 10

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

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

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
Fig 3. Endothelium of a 68-year-old man, demonstrating marked of endothelial function and corneal edema.
degree of precipitates on the endothelium four and one,half years A similar phenomenon was noted on examination of
following intraocular lens implantation using a Worst-Medallion lens. the postoperative endothelial cell morphology. Patients
Cell density, 842 cells/mm2. who developed corneal edema demonstrated marked
abnormality in cell shape in a greater number of eyes,
ation of corneal endothelium. No significant difference when compared to those patients who maintained clear
existed in the preoperative mean endothelial cell density corneas.
between those eyes which ultimately developed corneal In some eyes, chronic low-grade inflammation may
edema following IOL implantation and those which have been responsible for the ultimate demise of the
maintained clinically clear corneas. Similarly, no signif- cornea. This is evidenced by the increase in the incidence
icant difference was seen in the percentage of postoper- of corneal edema in eyes which demonstrated moderate
ative cell loss between the two groups. Thus, endothelial to severe degree of precipitation on the endothelium.
cell density in the range seen in this study did not The quantity of precipitates may be an index of the
appear to be a major determinant of the fate of corneas degree of chronicity of inflammation. Both inflammation
subjected to surgical trauma. and precipitates may lead to a diminution in endothelial
The coefficient of variation in cell area was examined. function which, in tum, leads to corneal decompensation.
The value is an index of the variation in cell size which Close follow-up of patients demonstrating these changes
represents one of the facets of cellular pleomorphism. is warranted to prevent irreversible changes. The effect
Analysis of these data demonstrated that the mean of precipitation or inflammation may be more deleterious
values between the two groups differed significantly with to the endothelial layer, with marked abnormality of
the group that developed corneal edema demonstrating cell shape.
an obviously greater degree of variation in cell size. This study suggests that marked variation in endothe-
From this, it appears that corneas with greater degree of lial cell morphology represents an aberrant endothelium
variation in cell size (polymegethism) are more vulnerable which is functionally less competent. Greater attention
to surgical trauma and have less functional reserve. This must be devoted to this feature in the analysis of
observation confirms our earlier observations on IOL specular photomicrographs in patients where major in-
patients;4 this morphological parameter deserves close traocular surgical intervention is contemplated. This
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 Fig 4. Corneal endothelium demonstrating abnormalities in cell shape
functions are compromised in the endothelium of that in a 70-year-old man, three and one-half years following intraocular
given cornea. Marked variation in cell size represents lens implantation with a Worst-Medallion lens. Cell density, 840 cells/
an aberration in cell morphology. Such an aberration mm2 Note the absence of the regular polygonal appearance of the
may result in diminished functional ability. Large cells corneal endothelium.

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OPHTHALMOLOGY OCTOBER 1984 VOLUME 91 NUMBER 10

information may also have application in the assessment 2. Rao GN, Stevens RE, Harris JK, Aquavella JV. Longterm changes
of donor corneas prior to corneal transplantation. in corneal endothelium following intraocular lens implantation. Oph-
thalmology 1981; 88:386-97.
3. Kraft MG, Sanders DR, Lieberman HL. Monitoring for continuing
ACKNOWLEDGMENTS endothelial cell loss with cataract extraction and intraocular lens
implantation. Ophthalmology 1982; 89:30-4.
Alex Martens of Bausch and Lomb Company provided 4. Rao GN, Shaw EL, Arthur EJ, Aquavella JV. Endothelial cell
assistance with image analysis. Gangaji Maguluri of the De- morphology and corneal deturgescence. Ann Ophthalmol 1979;
partment of Statistics at the University of Rochester provided 11:885-99.
the statistical analylsis. 5. Rao GN, Shaw EL, Stevens RE, Aquavella JV. Automated pattern
analysis of corneal endothelium. Ophthalmology 1979; 86: 1367-73.
6. Rao GN, Shaw EL, Arthur E, Aquavella JV. Morphological appearance
REFERENCES of the healing corneal endothelium. Arch Ophthalmol 1978; 96:2027-
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1. Bourne WM, Kaufrnan HE. Endothelial damage associated with 7. Hofter KJ. Vertical endothelial cell disparity. Am J Ophthalmol
intraocular lenses. Am J Ophthalmol 1976; 81 :482-5. 1979;87:344-9.

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