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Clinical Study of Fuchs Corneal Endothelial Dystrophy Leading to Penetrating Keratoplasty:  A 30-Year Experience FREE

Natalie A. Afshari, MD; Aaron B. Pittard, MD; Adnan Siddiqui, BS; Gordon K. Klintworth, MD, PhD
[+] Author Affiliations

Author Affiliations: Departments of Ophthalmology (Drs Afshari, Pittard, and Klintworth and Mr Siddiqui) and Pathology (Dr Klintworth), Duke University Medical Center, Durham, NC.


Arch Ophthalmol. 2006;124(6):777-780. doi:10.1001/archopht.124.6.777.
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Objective  To review 30 years' clinical experience with Fuchs corneal endothelial dystrophy leading to penetrating keratoplasty (PK).

Methods  We reviewed the clinical records of patients diagnosed histopathologically as having Fuchs corneal endothelial dystrophy who underwent PK at Duke University Medical Center between January 1, 1972, and December 31, 2001. This observational case series included 424 patients (546 eyes).

Results  Women represented 77.6% of patients. Mean age at the time of PK for all patients was 69.2 years. Bilateral PK was required in 28.8% of patients, and the mean interval between the 2 PKs was 3.2 years. There was no difference with regard to sex in the likelihood of requiring bilateral PK (P = .59). Among 376 documented family histories, 13.6% were known to be positive for Fuchs dystrophy. Patients with a positive family history underwent PK a mean of 5 years earlier (P<.002) and were more likely to require bilateral PK (P<.003). Patients who underwent bilateral PK were twice as likely to have a positive family history compared with those undergoing unilateral PK (P<.001). Mean visual acuities at corneal thicknesses of 539 to 650 μm, 651 to 750 μm, and greater than 750 μm were 20/60, 20/60, and 20/80, respectively. Patients who underwent bilateral PK and had a preceding cataract extraction on 1 eye required PK of the pseudophakic eye on average 3.2 years earlier than the fellow eye. The mean time from cataract extraction to PK was 2.2 years.

Conclusions  This large study affirms that Fuchs dystrophy is a disorder of aging that predominantly affects women (3.5:1) and is often familial. Pachymetry-determined corneal thickness was a poor predictor of visual acuity until extreme levels of corneal edema were reached. Cataract extraction in an eye with Fuchs dystrophy leads to earlier PK.

Figures in this Article

Fuchs corneal endothelial dystrophy is a common disorder of aging characterized by central corneal guttae followed by stromal edema that may result in decreased visual acuity (VA) and pain.13 Although the basic cause has yet to be determined, the principal defect is a decline in the number of functional endothelial cells.2,4 Other histopathologic findings may include subepithelial bullae and thickening of the Descemet membrane.2,5 The disorder is slowly progressive and bilateral but frequently asymmetric. Women are predominantly affected and familial clustering is common, suggesting an autosomal dominant inheritance and incomplete penetrance.68 The age distribution is wide, although the typical symptomatic onset is in the fifth or sixth decade of life, preceded several years earlier by clinical evidence of the disease.2 Medical management may be attempted; however, most patients ultimately require penetrating keratoplasty (PK).1 Fuchs dystrophy accounts for a tenth to a quarter of all corneal transplantations.916

Because few studies of Fuchs dystrophy exist, we reviewed the clinical records on 546 eyes from 424 patients with Fuchs dystrophy who underwent PK at our institution during the past 3 decades.

During the 30 years between January 1, 1972, and December 31, 2001, 710 patients with the histopathologic diagnosis of Fuchs dystrophy had undergone PK at Duke University Eye Center. All histopathologic diagnoses were confirmed by one ophthalmic pathologist (G.K.K.). The same criteria were used to diagnose each specimen: scant endothelial cells, corneal guttae, and thickening of the Descemet membrane. The medical records of 424 patients were available for review with institutional review board approval. This equated to reports on 546 eyes because some of these patients had undergone bilateral PK. From these records, the following data were extracted: (1) age of the patient at the time of PK in each eye; (2) sex; (3) preoperative VA; (4) date of previous cataract extraction (CE), if done; (5) family history, defined as the presence of Fuchs dystrophy in any member who is genetically related to the patient; (6) pachymetry findings; (7) preoperative clinical diagnosis; (8) histopathologic diagnosis; and (9) time interval between bilateral PKs. Family history and pachymetry results were not always available, particularly in older records.

We analyzed the records of patients who had undergone previous CE to help determine whether this procedure plays a role in accelerating the progression of Fuchs dystrophy. One group consisted of patients who underwent bilateral PK and a preceding unilateral CE. In that group, the time from CE to PK was recorded. Another group consisted of patients who underwent unilateral PK and a preceding unilateral CE. From these patients we determined the percentage of cases in which the CE was performed in the eye that later required PK.

We analyzed preoperative age, VA, number of eyes requiring PK, and family history and compared the results between men and women. We examined the same data in patients with a documented family history of Fuchs dystrophy to determine whether these patients were more severely affected. Having a blood relative who had known Fuchs dystrophy or had undergone PK was considered a positive family history.

When pachymetry data were available, readings were compared between the eyes that had and had not undergone operation. Eyes with previously grafted corneas were excluded.

Our findings are summarized in the Table. A single ophthalmic pathologist (G.K.K.) confirmed the diagnosis of Fuchs dystrophy in all 546 eyes using the same pathologic criteria. In 64 (11.7%) of the 546 eyes studied, the patient was clinically diagnosed as having pseudophakic or aphakic bullous keratopathy.

Table Graphic Jump LocationTable. Findings in Patients With Fuchs Dystrophy
SEX COMPARISON

Of the 424 patients studied, 329 (77.6%) were women, which equated to a female-male ratio of 3.5:1. At the time of PK, the mean ages for men and women were 66.3 and 70.2 years, respectively, which was a statistically significant difference of 4 years (P = .002). There was no difference with regard to sex in the likelihood of requiring bilateral PK (P<.59) or having a family history of Fuchs dystrophy (P<.72). The mean preoperative corneal thickness was greater in men by 23 μm.

FAMILY HISTORY

Family histories of 376 patients (88.7%) were documented in the medical records for review. Among those documented, 51 (13.6%) were positive for 1 (33 patients [65%]) or more (18 patients [35%]) blood relatives who had known Fuchs dystrophy or had undergone PK. Within this group with a positive family history, 41 (80%) were women and 10 (20%) were men. In addition, 21 patients in this group (41%) required bilateral PK, and the total number of eyes in this group was 72 (56 eyes in women and 16 eyes in men). The mean age at first PK was 64.8 years. Visual acuity was less than 20/40 in 75.4% and less than 20/100 in 18.8%. Pachymetry of the cornea indicated a corneal thickness of 679 μm in the operated-on eye and 652 μm in the fellow eye.

These 51 patients underwent PK a mean of 5 years earlier (at 64.8 vs 69.8 years; P<.002) and were more likely to require bilateral PK (21 patients [41.2%] vs 71 [21.8%]; P<.003) than were patients with no family history of Fuchs dystrophy. Patients who underwent bilateral PK were twice as likely as those who underwent unilateral PK to have a positive family history (21.1% vs 9.2% of patients; P<.001) (Table).

BILATERAL VS UNILATERAL PK

Of the 424 patients studied, the mean age at the time of the first PK was 69.2 years. One hundred twenty-two patients (28.8%) required bilateral PK; 97 (79.5%) of 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 in the second eye. The mean interval between the 2 procedures was 3.2 years. Of the remaining patients who underwent a unilateral PK, 76.8% were female and the mean age at PK was 70.8 years.

CATARACT EXTRACTION

We identified 17 patients who had undergone bilateral PK and unilateral CE. In 13 (76%) of these patients, the eye that underwent CE required PK earlier than the fellow eye by an mean of 3.2 years. The mean interval between CE and PK was 2.2 years. One hundred seventy patients underwent unilateral PK and an earlier unilateral CE. In 152 (89.4%) of these patients, the CE was performed in the eye that later required PK. Overall, of the 424 clinical charts reviewed, 187 (34.2%) of the 546 eyes had undergone a previous CE (Figure 1).

Place holder to copy figure label and caption
Figure 1.

Relationship of cataract extraction (CE) and penetrating keratoplasty (PK). A, In patients who had bilateral PK and unilateral CE, the 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 unilateral PK and a preceding unilateral CE.

Graphic Jump Location
VISUAL ACUITY

Best-corrected VA was measured at the last visit before corneal transplantation, and Figure 2 illustrates the distribution of VAs among these patients. The mean VA overall was 20/64.

Place holder to copy figure label and caption
Figure 2.

Distribution of best-corrected visual acuity (BCVA) in the operated-on eye at the time of penetrating keratoplasty.

Graphic Jump Location
PACHYMETRY

Pachymetry measurements were available in 259 eyes (47.4%) (Figure 3). Corneal thickness ranged from 539 to 940 μm, with a mean of 681 μm at the time of PK and 618 μm in the fellow eye. Corneal thicknesses and corresponding mean VAs were: 539 to 650 μm, 20/60; 651 to 750 μm, 20/60; and greater than 750 μm, 20/80. In the overall analysis of pachymetry data and VA, we found no linear decline in VA, as one might expect with increasing corneal thickness. However, at corneal thicknesses of approximately 775 μm and greater, the mean VA was 20/100, compared with 20/60 below that level (P<.004).

Place holder to copy figure label and caption
Figure 3.

Correlation of pachymetry findings and visual acuity at the time of penetrating keratoplasty. LogMAR indicates logarithm of the minimal angle of resolution.

Graphic Jump Location

Fuchs dystrophy is a disorder predominantly affecting women, as demonstrated in studies beginning with Ernst Fuchs' original description of the disease.17 Our finding of a female-male ratio of 3.5:1 confirms that observation. The reasons behind this sex-based discrepancy have not been established, although a few theories have been postulated, including embryological and hormonal mechanisms.1 To draw conclusions about sex and disease severity, we analyzed age at first PK and mean preoperative VA. Although men were an average of 4 years younger than women at the time of PK, and although the preoperative corneal thickness was slightly greater in men (by 23 μm), the mean preoperative VA was somewhat better in men. It is possible that the PKs were performed at an earlier stage of this disease in men. However, there was no difference with regard to sex in the likelihood of requiring bilateral PK or of having a family history of Fuchs dystrophy.

Although corneal thickness is commonly used as a measurement of disease progression, pachymetry findings are highly variable and do not seem to be a reliable indicator of VA. A linear correlation between VA and pachymetry values was not found. However, there was a statistically significant decline in VA at extreme levels of corneal edema (ie, at ≥775 μm). There may be a critical level of corneal edema beyond which VA drops off precipitously.

Familial clustering of Fuchs dystrophy is well documented.68 Of the 424 patients studied, 376 had family histories documented in the medical records. Among those documented, it is impossible to know the extent to which the issue of family history of Fuchs dystrophy was pressed. Also, some negative family histories turned out to be positive when the issue was explored more thoroughly in recent follow-up clinic visits. For these reasons, the factor of 13.6% of patients having positive family histories, although significant, is probably artificially low. Two observations suggest that patients with a family history of Fuchs dystrophy may be more severely affected. First, PK was performed on average 5 years earlier in patients with a positive family history. Second, patients with bilateral PK were twice as likely as those with unilateral PK to have a positive family history. We found no sex-specific difference in the likelihood of having a family history of the disease.

This 30-year study includes extracapsular CE as well as phacoemulsification, and we did not account for surgical method in our analysis. Nevertheless, the role of CE in the progression of corneal decompensation in patients with Fuchs dystrophy was significant. One third of the eyes studied had undergone a previous CE. Of those patients who underwent bilateral PK and a preceding unilateral CE, the eye that underwent CE was 3 times more likely to require PK before the fellow eye by a mean of 3.2 years. Among patients who underwent unilateral PK and a preceding unilateral CE, 89.4% of the CEs were performed on the eye that later required PK. The small but significant percentage of patients with a preoperative diagnosis of pseudophakic bullous keratopathy underscores the difficulty in diagnosing Fuchs dystrophy in a patient after CE. Clearly, CE remains a method of unmasking Fuchs dystrophy.

As a disorder of the elderly, Fuchs dystrophy will likely continue to increase in prevalence in an aging population. Several issues will require more investigation. Alternative therapies such as deep lamellar endothelial transplantation may provide promise in the advancement of treatment for these patients. Furthermore, the familial clustering of Fuchs dystrophy continues to suggest a genetic predisposition for this disorder. One study18 found mutations in a gene encoding a portion of type VIII collagen, a component of endothelial basement membranes. Genetic and perhaps environmental factors may play a role in the relatively large number of individuals with Fuchs dystrophy at our institution. Further studies are needed to elucidate the cause of the disease as a possible guide for therapy or prevention.

Correspondence: Natalie A. Afshari, MD, Department of Ophthalmology, Duke University Eye Center, Duke University Medical Center, DUMC Box 3802, Durham, NC 27710 (afsha003@mc.duke.edu).

Submitted for Publication: November 23, 2004; final revision received February 15, 2005; accepted February 15, 2005.

Financial Disclosure: None.

Funding/Support: Dr Afshari has received a Career Development Award from Research to Prevent Blindness.

Adamis  APFilatov  VTripathi  BJTripathi  RC Fuchs' endothelial dystrophy of the cornea. Surv Ophthalmol 1993;38149- 168
PubMed
Borboli  SColby  K Mechanisms of disease: Fuchs' endothelial dystrophy. Ophthalmol Clin North Am 2002;1517- 25
PubMed
Wilson  SEBourne  WMO’Brien  PCBrubaker  RF Endothelial function and aqueous humor flow rate in patients with Fuchs' dystrophy. Am J Ophthalmol 1988;106270- 278
PubMed
Wilson  SEBourne  WM Fuchs' dystrophy. Cornea 1988;72- 18
PubMed
Mustonen  RKMcDonald  MBSrivannaboon  STan  ALDoubrava  MWKim  CK In vivo confocal microscopy of Fuchs' endothelial dystrophy. Cornea 1998;17493- 503
PubMed
Cross  HEMaumenee  AECantolino  SJ Inheritance of Fuchs' endothelial dystrophy. Arch Ophthalmol 1971;85268- 272
PubMed
Magovern  MBeauchamp  GRMcTigue  JWFine  BSBaumiller  RC Inheritance of Fuchs' combined dystrophy. Ophthalmology 1979;861897- 1920
PubMed
Rosenblum  PStark  WJMaumenee  IHHirst  LWMaumenee  E Hereditary Fuchs' dystrophy. Am J Ophthalmol 1980;90455- 462
PubMed
Maeno  ANaor  JLee  HMHunter  WSRootman  DS Three decades of corneal transplantation: indications and patient characteristics. Cornea 2000;197- 11
PubMed
Dobbins  KRBPrice  FW  JrWhitson  WE Trends in the indications for penetrating keratoplasty in the midwestern United States. Cornea 2000;19813- 816
PubMed
Lois  NKowal  VOCohen  EJ  et al.  Indications for penetrating keratoplasty and associated procedures, 1989-1995. Cornea 1997;16623- 629
PubMed
Cursiefen  CKüchle  MNaumann  GOH Changing indications for penetrating keratoplasty: histopathology of 1,250 corneal buttons. Cornea 1998;17468- 470
PubMed
Brady  SERapuano  CJArentsen  JJCohen  EJLaibson  PR Clinical indications for and procedures associated with penetrating keratoplasty, 1983-1988. Am J Ophthalmol 1989;108118- 122
PubMed
Lois  NKowal  VOCohen  EJ  et al.  Indications for penetrating keratoplasty and associated procedures, 1989-1993. Cornea 1997;16623- 629
PubMed
Al-Yousuf  NMavrikakis  IMavrikakis  EDaya  SM Penetrating keratoplasty: indications over a 10 year period. Br J Ophthalmol 2004;88998- 1001
PubMed
Kang  PCKlintworth  GKKim  T  et al.  Trends in the indications for penetrating keratoplasty, 1980-2001. Cornea 2005;24801- 803
PubMed
Fuchs  E Dystrophia epithelialis corneae. Albrecht Von Graefes Arch Klin Exp Ophthalmol 1910;76478- 508
Biswas  SMunier  FLYardley  J  et al.  Missense mutations in COL8A2, the gene encoding the α2 chain of type VIII collagen, cause two forms of corneal endothelial dystrophy. Hum Mol Genet 2001;102415- 2423
PubMed

Figures

Place holder to copy figure label and caption
Figure 1.

Relationship of cataract extraction (CE) and penetrating keratoplasty (PK). A, In patients who had bilateral PK and unilateral CE, the 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 unilateral PK and a preceding unilateral CE.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Distribution of best-corrected visual acuity (BCVA) in the operated-on eye at the time of penetrating keratoplasty.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Correlation of pachymetry findings and visual acuity at the time of penetrating keratoplasty. LogMAR indicates logarithm of the minimal angle of resolution.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable. Findings in Patients With Fuchs Dystrophy

References

Adamis  APFilatov  VTripathi  BJTripathi  RC Fuchs' endothelial dystrophy of the cornea. Surv Ophthalmol 1993;38149- 168
PubMed
Borboli  SColby  K Mechanisms of disease: Fuchs' endothelial dystrophy. Ophthalmol Clin North Am 2002;1517- 25
PubMed
Wilson  SEBourne  WMO’Brien  PCBrubaker  RF Endothelial function and aqueous humor flow rate in patients with Fuchs' dystrophy. Am J Ophthalmol 1988;106270- 278
PubMed
Wilson  SEBourne  WM Fuchs' dystrophy. Cornea 1988;72- 18
PubMed
Mustonen  RKMcDonald  MBSrivannaboon  STan  ALDoubrava  MWKim  CK In vivo confocal microscopy of Fuchs' endothelial dystrophy. Cornea 1998;17493- 503
PubMed
Cross  HEMaumenee  AECantolino  SJ Inheritance of Fuchs' endothelial dystrophy. Arch Ophthalmol 1971;85268- 272
PubMed
Magovern  MBeauchamp  GRMcTigue  JWFine  BSBaumiller  RC Inheritance of Fuchs' combined dystrophy. Ophthalmology 1979;861897- 1920
PubMed
Rosenblum  PStark  WJMaumenee  IHHirst  LWMaumenee  E Hereditary Fuchs' dystrophy. Am J Ophthalmol 1980;90455- 462
PubMed
Maeno  ANaor  JLee  HMHunter  WSRootman  DS Three decades of corneal transplantation: indications and patient characteristics. Cornea 2000;197- 11
PubMed
Dobbins  KRBPrice  FW  JrWhitson  WE Trends in the indications for penetrating keratoplasty in the midwestern United States. Cornea 2000;19813- 816
PubMed
Lois  NKowal  VOCohen  EJ  et al.  Indications for penetrating keratoplasty and associated procedures, 1989-1995. Cornea 1997;16623- 629
PubMed
Cursiefen  CKüchle  MNaumann  GOH Changing indications for penetrating keratoplasty: histopathology of 1,250 corneal buttons. Cornea 1998;17468- 470
PubMed
Brady  SERapuano  CJArentsen  JJCohen  EJLaibson  PR Clinical indications for and procedures associated with penetrating keratoplasty, 1983-1988. Am J Ophthalmol 1989;108118- 122
PubMed
Lois  NKowal  VOCohen  EJ  et al.  Indications for penetrating keratoplasty and associated procedures, 1989-1993. Cornea 1997;16623- 629
PubMed
Al-Yousuf  NMavrikakis  IMavrikakis  EDaya  SM Penetrating keratoplasty: indications over a 10 year period. Br J Ophthalmol 2004;88998- 1001
PubMed
Kang  PCKlintworth  GKKim  T  et al.  Trends in the indications for penetrating keratoplasty, 1980-2001. Cornea 2005;24801- 803
PubMed
Fuchs  E Dystrophia epithelialis corneae. Albrecht Von Graefes Arch Klin Exp Ophthalmol 1910;76478- 508
Biswas  SMunier  FLYardley  J  et al.  Missense mutations in COL8A2, the gene encoding the α2 chain of type VIII collagen, cause two forms of corneal endothelial dystrophy. Hum Mol Genet 2001;102415- 2423
PubMed

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