CLINICAL SCIENCES

Clinical Study of Fuchs Corneal Endothelial

Dystrophy Leading to Penetrating Keratoplasty
A 30-Year Experience
Natalie A. Afshari, MD; Aaron B. Pittard, MD; Adnan Siddiqui, BS; Gordon K. Klintworth, MD, PhD

Objective: To review 30 years’ clinical experience with to require bilateral PK (P⬍.003). Patients who underwent
Fuchs corneal endothelial dystrophy leading to penetrat- bilateral PK were twice as likely to have a positive family
ing keratoplasty (PK). history compared with those undergoing unilateral PK
(P⬍.001). Mean visual acuities at corneal thicknesses of
Methods: We reviewed the clinical records of patients 539 to 650 µm, 651 to 750 µm, and greater than 750 µm
diagnosed histopathologically as having Fuchs corneal were 20/60, 20/60, and 20/80, respectively. Patients who
endothelial dystrophy who underwent PK at Duke underwent bilateral PK and had a preceding cataract ex-
University Medical Center between January 1, 1972, and traction on 1 eye required PK of the pseudophakic eye on
December 31, 2001. This observational case series average 3.2 years earlier than the fellow eye. The mean time
included 424 patients (546 eyes). from cataract extraction to PK was 2.2 years.

Results: Women represented 77.6% of patients. Mean age Conclusions: This large study affirms that Fuchs dys-
at the time of PK for all patients was 69.2 years. Bilateral trophy is a disorder of aging that predominantly affects
PK was required in 28.8% of patients, and the mean inter- women (3.5:1) and is often familial. Pachymetry-
val between the 2 PKs was 3.2 years. There was no differ- determined corneal thickness was a poor predictor of vi-
ence with regard to sex in the likelihood of requiring bi- sual acuity until extreme levels of corneal edema were
lateral PK (P = .59). Among 376 documented family reached. Cataract extraction in an eye with Fuchs dys-
histories, 13.6% were known to be positive for Fuchs dys- trophy leads to earlier PK.
trophy. Patients with a positive family history underwent
PK a mean of 5 years earlier (P⬍.002) and were more likely Arch Ophthalmol. 2006;124:777-780

F
UCHS CORNEAL ENDOTHE - mately require penetrating keratoplasty
lial dystrophy is a common (PK).1 Fuchs dystrophy accounts for a
disorder of aging character- tenth to a quarter of all corneal transplan-
ized by central corneal gut- tations.9-16
tae followed by stromal Because few studies of Fuchs dystro-
edema that may result in decreased vi- phy exist, we reviewed the clinical rec-
sual acuity (VA) and pain.1-3 Although the ords on 546 eyes from 424 patients with
basic cause has yet to be determined, the Fuchs dystrophy who underwent PK at our
principal defect is a decline in the num- institution during the past 3 decades.
ber of functional endothelial cells.2,4 Other
histopathologic findings may include sub-
epithelial bullae and thickening of the Des- METHODS
cemet membrane.2,5 The disorder is slowly
progressive and bilateral but frequently During the 30 years between January 1, 1972,
asymmetric. Women are predominantly af- and December 31, 2001, 710 patients with the
fected and familial clustering is common, histopathologic diagnosis of Fuchs dystrophy
suggesting an autosomal dominant inher- had undergone PK at Duke University Eye Cen-
itance and incomplete penetrance.6-8 The ter. All histopathologic diagnoses were con-
Author Affiliations: firmed by one ophthalmic pathologist (G.K.K.).
age distribution is wide, although the typi- The same criteria were used to diagnose each
Departments of Ophthalmology
(Drs Afshari, Pittard, and cal symptomatic onset is in the fifth or specimen: scant endothelial cells, corneal gut-
Klintworth and Mr Siddiqui) sixth decade of life, preceded several years tae, and thickening of the Descemet mem-
and Pathology (Dr Klintworth), earlier by clinical evidence of the dis- brane. The medical records of 424 patients were
Duke University Medical ease.2 Medical management may be at- available for review with institutional review
Center, Durham, NC. tempted; however, most patients ulti- board approval. This equated to reports on 546

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 Table. Findings in Patients With Fuchs Dystrophy

Patient Group

All Positive Bilateral Unilateral Previous Cataract

Criteria Patients Women Men Family History PK PK Extraction
Patients, No. 424 329 95 51 122 302 NA
Eyes, No. 546 426 120 72 244 302 187
Women, No. 77.6* ... ... 41 97 232 156
Men, No. 22.4* ... ... 10 25 70 31
Age at first PK, mean, y 69.2 70.2 66.3 64.8 65.6 70.8 73.5
BCVA ⬍20/40, % 83.1 85.7 74.1 75.4 78.0 87.9 73.0
BCVA ⬍20/100, % 36.3 37.8 31.6 18.8 29.6 41.9 35.7
Positive family history, % 13.6 14.4 12.8 ... 21.1 9.2 7.4
Bilateral PK, % 30.0 29.3 26.5 41.2 ... ... 10.4

Abbreviations: BCVA, best-corrected visual acuity; PK, penetrating keratoplasty, ellipses, not applicable.
*Given as percentage of patients.

eyes because some of these patients had undergone bilateral cant difference of 4 years (P=.002). There was no dif-
PK. From these records, the following data were extracted: ference with regard to sex in the likelihood of requiring
(1) age of the patient at the time of PK in each eye; (2) sex; bilateral PK (P⬍.59) or having a family history of Fuchs
(3) preoperative VA; (4) date of previous cataract extraction dystrophy (P⬍.72). The mean preoperative corneal thick-
(CE), if done; (5) family history, defined as the presence of Fuchs
ness was greater in men by 23 µm.
dystrophy in any member who is genetically related to the pa-
tient; (6) pachymetry findings; (7) preoperative clinical diag-
nosis; (8) histopathologic diagnosis; and (9) time interval be- FAMILY HISTORY
tween bilateral PKs. Family history and pachymetry results were
not always available, particularly in older records. Family histories of 376 patients (88.7%) were docu-
We analyzed the records of patients who had undergone pre- mented in the medical records for review. Among those
vious CE to help determine whether this procedure plays a role
in accelerating the progression of Fuchs dystrophy. One group
documented, 51 (13.6%) were positive for 1 (33 pa-
consisted of patients who underwent bilateral PK and a pre- tients [65%]) or more (18 patients [35%]) blood rela-
ceding unilateral CE. In that group, the time from CE to PK tives who had known Fuchs dystrophy or had under-
was recorded. Another group consisted of patients who under- gone PK. Within this group with a positive family history,
went unilateral PK and a preceding unilateral CE. From these 41 (80%) were women and 10 (20%) were men. In ad-
patients we determined the percentage of cases in which the dition, 21 patients in this group (41%) required bilat-
CE was performed in the eye that later required PK. eral PK, and the total number of eyes in this group was
We analyzed preoperative age, VA, number of eyes requir- 72 (56 eyes in women and 16 eyes in men). The mean
ing PK, and family history and compared the results between age at first PK was 64.8 years. Visual acuity was less than
men and women. We examined the same data in patients with 20/40 in 75.4% and less than 20/100 in 18.8%. Pachym-
a documented family history of Fuchs dystrophy to determine
whether these patients were more severely affected. Having a
etry of the cornea indicated a corneal thickness of 679
blood relative who had known Fuchs dystrophy or had under- µm in the operated-on eye and 652 µm in the fellow eye.
gone PK was considered a positive family history. These 51 patients underwent PK a mean of 5 years ear-
When pachymetry data were available, readings were com- lier (at 64.8 vs 69.8 years; P⬍.002) and were more likely
pared between the eyes that had and had not undergone op- to require bilateral PK (21 patients [41.2%] vs 71 [21.8%];
eration. Eyes with previously grafted corneas were excluded. P⬍.003) than were patients with no family history of
Fuchs dystrophy. Patients who underwent bilateral PK
RESULTS were twice as likely as those who underwent unilateral
PK to have a positive family history (21.1% vs 9.2% of
Our findings are summarized in the Table. A single oph- patients; P⬍.001) (Table).
thalmic pathologist (G.K.K.) confirmed the diagnosis of
Fuchs dystrophy in all 546 eyes using the same patho- BILATERAL VS UNILATERAL PK
logic criteria. In 64 (11.7%) of the 546 eyes studied, the
patient was clinically diagnosed as having pseudopha- Of the 424 patients studied, the mean age at the time of
kic or aphakic bullous keratopathy. the first PK was 69.2 years. One hundred twenty-two
patients (28.8%) required bilateral PK; 97 (79.5%) of
SEX COMPARISON them were women. Their mean age was 65.6 years at
the time of the first PK and 68.7 years at the time of PK
Of the 424 patients studied, 329 (77.6%) were women, in the second eye. The mean interval between the 2 pro-
which equated to a female-male ratio of 3.5:1. At the time cedures was 3.2 years. Of the remaining patients who
of PK, the mean ages for men and women were 66.3 and underwent a unilateral PK, 76.8% were female and the
70.2 years, respectively, which was a statistically signifi- mean age at PK was 70.8 years.

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 A 60

14
50
12

Percentage of Eyes
10 40
No. of Eyes

8
30
6

4 20

2
10
0
Phakic Eye Pseudophakic Eye
Underwent PK First Underwent PK First 0
>20/40 20/50 to 20/125 to 20/250 to <20/400
20/100 20/200 20/400
B
BCVA
160

140
Figure 2. Distribution of best-corrected visual acuity (BCVA) in the
120 operated-on eye at the time of penetrating keratoplasty.
100
No. of Eyes

80

60 3.0

40
2.5
20

Visual Acuity, LogMAR

0
2.0
PK Contralateral PK Ipsilateral
to CE to CE
1.5

Figure 1. Relationship of cataract extraction (CE) and penetrating

keratoplasty (PK). A, In patients who had bilateral PK and unilateral CE, the 1.0
pseudophakic eye was more likely to undergo PK first. B, The likelihood of
PK being performed ipsilateral to a preceding CE among eyes that underwent 0.5
unilateral PK and a preceding unilateral CE.

0
CATARACT EXTRACTION 500 600 700 800 900 1000
Corneal Thickness, µm

We identified 17 patients who had undergone bilateral

Figure 3. Correlation of pachymetry findings and visual acuity at the time of
PK and unilateral CE. In 13 (76%) of these patients, the penetrating keratoplasty. LogMAR indicates logarithm of the minimal angle
eye that underwent CE required PK earlier than the fel- of resolution.
low eye by an mean of 3.2 years. The mean interval be-
tween CE and PK was 2.2 years. One hundred seventy
patients underwent unilateral PK and an earlier unilat- no linear decline in VA, as one might expect with in-
eral CE. In 152 (89.4%) of these patients, the CE was per- creasing corneal thickness. However, at corneal thick-
formed in the eye that later required PK. Overall, of the nesses of approximately 775 µm and greater, the mean
424 clinical charts reviewed, 187 (34.2%) of the 546 eyes VA was 20/100, compared with 20/60 below that level
had undergone a previous CE (Figure 1). (P⬍.004).

VISUAL ACUITY COMMENT

Best-corrected VA was measured at the last visit before Fuchs dystrophy is a disorder predominantly affecting
corneal transplantation, and Figure 2 illustrates the dis- women, as demonstrated in studies beginning with Ernst
tribution of VAs among these patients. The mean VA over- Fuchs’ original description of the disease.17 Our finding
all was 20/64. of a female-male ratio of 3.5:1 confirms that observa-
tion. The reasons behind this sex-based discrepancy have
PACHYMETRY not been established, although a few theories have been
postulated, including embryological and hormonal mecha-
Pachymetry measurements were available in 259 eyes nisms.1 To draw conclusions about sex and disease se-
(47.4%) (Figure 3). Corneal thickness ranged from 539 verity, we analyzed age at first PK and mean preopera-
to 940 µm, with a mean of 681 µm at the time of PK and tive VA. Although men were an average of 4 years younger
618 µm in the fellow eye. Corneal thicknesses and cor- than women at the time of PK, and although the preop-
responding mean VAs were: 539 to 650 µm, 20/60; 651 erative corneal thickness was slightly greater in men (by
to 750 µm, 20/60; and greater than 750 µm, 20/80. In 23 µm), the mean preoperative VA was somewhat bet-
the overall analysis of pachymetry data and VA, we found ter in men. It is possible that the PKs were performed at

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an earlier stage of this disease in men. However, there netic predisposition for this disorder. One study18 found
was no difference with regard to sex in the likelihood of mutations in a gene encoding a portion of type VIII col-
requiring bilateral PK or of having a family history of lagen, a component of endothelial basement mem-
Fuchs dystrophy. branes. Genetic and perhaps environmental factors may
Although corneal thickness is commonly used as a play a role in the relatively large number of individuals
measurement of disease progression, pachymetry find- with Fuchs dystrophy at our institution. Further stud-
ings are highly variable and do not seem to be a reliable ies are needed to elucidate the cause of the disease as a
indicator of VA. A linear correlation between VA and possible guide for therapy or prevention.
pachymetry values was not found. However, there was a
statistically significant decline in VA at extreme levels of
corneal edema (ie, at ⱖ775 µm). There may be a critical Submitted for Publication: November 23, 2004; final
level of corneal edema beyond which VA drops off revision received February 15, 2005; accepted February
precipitously. 15, 2005.
Familial clustering of Fuchs dystrophy is well docu- Correspondence: Natalie A. Afshari, MD, Department of
mented.6-8 Of the 424 patients studied, 376 had family Ophthalmology, Duke University Eye Center, Duke
histories documented in the medical records. Among those University Medical Center, DUMC Box 3802, Durham,
documented, it is impossible to know the extent to which NC 27710 ([email protected]).
the issue of family history of Fuchs dystrophy was pressed. Financial Disclosure: None.
Also, some negative family histories turned out to be posi- Funding/Support: Dr Afshari has received a Career
tive when the issue was explored more thoroughly in re- Development Award from Research to Prevent Blindness.
cent follow-up clinic visits. For these reasons, the factor
of 13.6% of patients having positive family histories, al- REFERENCES
though significant, is probably artificially low. Two ob-
servations suggest that patients with a family history of 1. Adamis AP, Filatov V, Tripathi BJ, Tripathi RC. Fuchs’ endothelial dystrophy of
Fuchs dystrophy may be more severely affected. First, the cornea. Surv Ophthalmol. 1993;38:149-168.
2. Borboli S, Colby K. Mechanisms of disease: Fuchs’ endothelial dystrophy. Oph-
PK was performed on average 5 years earlier in patients thalmol Clin North Am. 2002;15:17-25.
with a positive family history. Second, patients with bi- 3. Wilson SE, Bourne WM, O’Brien PC, Brubaker RF. Endothelial function and aque-
lateral PK were twice as likely as those with unilateral ous humor flow rate in patients with Fuchs’ dystrophy. Am J Ophthalmol. 1988;
PK to have a positive family history. We found no sex- 106:270-278.
4. Wilson SE, Bourne WM. Fuchs’ dystrophy. Cornea. 1988;7:2-18.
specific difference in the likelihood of having a family 5. Mustonen RK, McDonald MB, Srivannaboon S, Tan AL, Doubrava MW, Kim CK.
history of the disease. In vivo confocal microscopy of Fuchs’ endothelial dystrophy. Cornea. 1998;
This 30-year study includes extracapsular CE as well 17:493-503.
as phacoemulsification, and we did not account for sur- 6. Cross HE, Maumenee AE, Cantolino SJ. Inheritance of Fuchs’ endothelial dystrophy.
gical method in our analysis. Nevertheless, the role of CE Arch Ophthalmol. 1971;85:268-272.
7. Magovern M, Beauchamp GR, McTigue JW, Fine BS, Baumiller RC. Inheritance
in the progression of corneal decompensation in pa- of Fuchs’ combined dystrophy. Ophthalmology. 1979;86:1897-1920.
tients with Fuchs dystrophy was significant. One third 8. Rosenblum P, Stark WJ, Maumenee IH, Hirst LW, Maumenee E. Hereditary Fuchs’
of the eyes studied had undergone a previous CE. Of those dystrophy. Am J Ophthalmol. 1980;90:455-462.
patients who underwent bilateral PK and a preceding uni- 9. Maeno A, Naor J, Lee HM, Hunter WS, Rootman DS. Three decades of corneal
transplantation: indications and patient characteristics. Cornea. 2000;19:7-11.
lateral CE, the eye that underwent CE was 3 times more 10. Dobbins KRB, Price FW Jr, Whitson WE. Trends in the indications for penetrat-
likely to require PK before the fellow eye by a mean of ing keratoplasty in the midwestern United States. Cornea. 2000;19:813-816.
3.2 years. Among patients who underwent unilateral PK 11. Lois N, Kowal VO, Cohen EJ, et al. Indications for penetrating keratoplasty and
and a preceding unilateral CE, 89.4% of the CEs were associated procedures, 1989-1995. Cornea. 1997;16:623-629.
performed on the eye that later required PK. The small 12. Cursiefen C, Küchle M, Naumann GOH. Changing indications for penetrating kera-
toplasty: histopathology of 1,250 corneal buttons. Cornea. 1998;17:468-470.
but significant percentage of patients with a preopera- 13. Brady SE, Rapuano CJ, Arentsen JJ, Cohen EJ, Laibson PR. Clinical indications
tive diagnosis of pseudophakic bullous keratopathy un- for and procedures associated with penetrating keratoplasty, 1983-1988. Am J
derscores the difficulty in diagnosing Fuchs dystrophy Ophthalmol. 1989;108:118-122.
in a patient after CE. Clearly, CE remains a method of 14. Lois N, Kowal VO, Cohen EJ, et al. Indications for penetrating keratoplasty and
associated procedures, 1989-1993. Cornea. 1997;16:623-629.
unmasking Fuchs dystrophy. 15. Al-Yousuf N, Mavrikakis I, Mavrikakis E, Daya SM. Penetrating keratoplasty: in-
As a disorder of the elderly, Fuchs dystrophy will likely dications over a 10 year period. Br J Ophthalmol. 2004;88:998-1001.
continue to increase in prevalence in an aging popula- 16. Kang PC, Klintworth GK, Kim T, et al. Trends in the indications for penetrating
tion. Several issues will require more investigation. Al- keratoplasty, 1980-2001. Cornea. 2005;24:801-803.
ternative therapies such as deep lamellar endothelial trans- 17. Fuchs E. Dystrophia epithelialis corneae. Albrecht Von Graefes Arch Klin Exp
Ophthalmol. 1910;76:478-508.
plantation may provide promise in the advancement of 18. Biswas S, Munier FL, Yardley J, et al. Missense mutations in COL8A2, the gene
treatment for these patients. Furthermore, the familial encoding the ␣2 chain of type VIII collagen, cause two forms of corneal endo-
clustering of Fuchs dystrophy continues to suggest a ge- thelial dystrophy. Hum Mol Genet. 2001;10:2415-2423.

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