Fuchs Dystrophy 

Fuchs Dystrophy – Introduction

• Slowly progressing ophthalmologic disorder of aging characterized by changes in corneal endothelium (guttae) leading to stromal edema with potential loss of visual acuity^(1,2)

Synonyms

•  Fuchs’ dystrophy
•  Fuchs corneal dystrophy
•  Fuchs’ corneal endothelial dystrophy
•  Fuchs’ endothelial dystrophy
•  Fuchs’ endothelial dystrophy of the cornea
•  endothelial dystrophy of the cornea
•  epithelial dystrophy of Fuchs
•  Fuchs’ epithelial endothelial dystrophy
•  late hereditary endothelial dystrophy
•  primary cornea guttata

Definitions

•  guttae – focal excrescences on endothelial surface of cornea⁽²⁾

Types

• course of disease can be divided into 4 stages, usually spanning 10-20 years⁽²⁾
  • stage 1
    •  usually asymptomatic
    •  thickened Descemet’s membrane
    •  central corneal guttae
    •  pigment dusting on posterior surface of cornea
    •  guttae appear as small droplets
  • stage 2
    •  painless transient decrease in vision when awakening
    •  morning blurring
    •  glare
    •  epithelial edema appears as fine microcysts on corneal surface
    •  stromal edema, seen as corneal thickening on slit lamp examination
  • stage 3
    •  painful episodes
    •  decrease in vision secondary to advanced corneal edema
    •  formation of bullae in epithelial and subepithelial layers
  • stage 4
    •  painless
    •  may have profound vision loss secondary to subepithelial scarring
    •  diffuse non-vascular subepithelial connective tissue seen

Epidemiology

Who Is Most Affected

• predominantly women^(1,2)
  •  77.6% were women in record review of 424 patients with Fuchs dystrophy who had penetrating keratoplasty⁽¹⁾
•  apparent on exam at age 30-40 years, with visual symptoms about 10 years later^(1,2)

Incidence/Prevalence

• about 1-4% patients with cataract may have Fuchs dystrophy
  •  primary cornea guttata (first stage of Fuchs dystrophy) found in 4 of 107 Japanese cataract patients (Jpn J Ophthalmol 1996;40(4):520)
  •  17 of 2,026 (0.8%) consecutive patients with senile cataracts diagnosed with Fuchs dystrophy in China between 1998-2001 (Chin Med J (Engl) 2005 Jul 5;118(13):1127)
•  9.1% incidence of Fuchs dystrophy among 11,598 registrants awaiting penetrating keratoplasty in France during 2000-2001 (J Fr Ophtalmol 2003 Nov;26(9):911)
• diagnosis of Fuchs dystrophy accounts for 10-25% of corneal transplantations⁽¹⁾
  •  23.2% incidence in cohort of 3,263 patients having 4,217 penetrating keratoplasties 1982-1996 at single institution in United States (Cornea 2000 Nov;19(6):813)
  •  14.8% incidence in 2,557 tissue samples of patients having penetrating keratoplasties 1992-1996 at German university (Cornea 1998 Sep;17(5):468)

Likely Risk Factors

•  familial clustering suggests genetic predisposition and autosomal dominant inheritance with incomplete penetrance^(1,2)

Possible Risk Factors

• evidence for association with COL8A1 and COL8A2 gene mutations limited and inconsistent
  •  possible mutation in COL8A2 reported to be associated with corneal endothelial dystrophy (Hum Mol Genet 2001 Oct 1;10(21):2415full-text)
  •  case-control study discounting COL8A1 and COL8A2 gene mutations as cause of late-onset familial Fuchs dystrophy can be found in Invest Ophthalmol Vis Sci 2006 Sep;47(9):3787full-text
•  genetic variation in TCF4 gene associated with typical Fuchs dystrophy in genomewide study (N Engl J Med 2010 Sep 9;363(11):1016), editorial can be found in N Engl J Med 2010 Sep 9;363(11):1072
•  L450W mutation associated with rare, early-onset familial Fuchs dystrophy in series of 3 patients (Trans Am Ophthalmol Soc 2006;104:85full-text)
•  inflammation, infection, trauma, toxic injury may trigger development in endothelium genetically predisposed to Fuchs dystrophy⁽²⁾

Associated Conditions

• Fuchs dystrophy reported to occur more frequently in patients with⁽²⁾
  •  cardiovascular disease
  •  age-related macular degeneration
  •  keratoconus
  •  essential blepharospasm
  •  axial hypermetropia (Br J Ophthalmol 1990 Oct;74(10):601PDF)

Etiology and Pathogenesis

Causes

•  unknown^(1,2)
•  may be associated with abnormalities in mitochondrial DNA⁽²⁾

Pathogenesis

•  dysfunction of endothelium resulting in guttae and stromal edema and subsequent loss of corneal transparency⁽¹⁾
• course of disease can be divided into 4 stages, usually spanning 10-20 years⁽²⁾
  • stage 1
    •  usually asymptomatic
    •  thickened Descemet’s membrane
    •  central corneal guttae
    •  pigment dusting on posterior surface of cornea
    •  guttae appear as small droplets
  • stage 2
    •  painless transient decrease in vision when awakening
    •  morning blurring
    •  glare
    •  epithelial edema appears as fine microcysts on corneal surface
    •  stromal edema, seen as corneal thickening on slit lamp examination
  • stage 3
    •  painful episodes
    •  decrease in vision secondary to advanced corneal edema
    •  formation of bullae in epithelial and subepithelial layers
  • stage 4
    •  painless
    •  may have profound vision loss secondary to subepithelial scarring
    •  diffuse non-vascular subepithelial connective tissue seen

History and Physical

History

Chief Concern (CC)

•  glare and transient blurring of vision when waking⁽²⁾
•  disruption of sight ranging from decrease in visual acuity to profound vision loss^(1,2)
•  eye pain^(1,2)

History of Present Illness (HPI)

•  10-20 year course of disease typical⁽²⁾

Family History (FH)

•  familial clustering suggests genetic predisposition and autosomal dominant inheritance with incomplete penetrance^(1,2)

Physical

HEENT

• findings on slit lamp exam⁽²⁾
  •  guttae on surface of central cornea
  •  pigment granules attached to endothelial cells may be seen
  •  presence of corneal edema

Diagnosis

Making the Diagnosis

• slit-lamp exam showing⁽²⁾
  •  corneal edema
  •  focal excrescences (guttae) on corneal endothelium in central cornea (although non-guttae forms have been noted)
• specular microscopy may be done as adjunct to clinical exam

Differential Diagnosis

•  Hassall-Henle bodies – guttae in peripheral cornea (a normal finding), whereas Fuchs dystrophy includes central guttae⁽²⁾
• other endothelial diseases of eye⁽²⁾
  • posterior polymorphous dystrophy
    •  no corneal guttae
    •  stromal opacities or epithelial edema rare
    •  no reduction in visual acuity
  • congenital hereditary endothelial dystrophy
    •  Descemet’s membrane is thinned
    •  endothelial cells absent or severely atrophic
  •  aphakic or pseudophakic bullous keratopathy
  • endothelial dysfunction and corneal edema due to
    •  interstitial keratitis
    •  keratitis, especially herpes simplex keratitis
    •  anterior uveitis
  • corneal inflammation due to
    •  infection
    •  endothelial trauma

Testing Overview

•  slit-lamp exam for diagnosis
•  visual acuity test
•  pachymetry (determination of corneal thickness)
•  specular microscopy

Other Diagnostic Testing

• in vivo specular microscopy⁽²⁾
  •  monitors number, quality, and density of endothelial cells of cornea
  • findings include
    •  reduced endothelial cell count
    •  increased endothelial cell size (polymegathism)
    •  variability in shape of endothelial cells (pleomorphism)
    •  multifocal hyporeflective guttae surrounded by hyperreflective endothelial cells

Management

Management Overview

•  stage 1 – no treatment required in absence of edema⁽²⁾
• stage 2 – treat edema⁽²⁾
  •  topical hyperosmotic agents such as sodium chloride solution
  • hairdryer
• stage 3 – treat edema (as above) and discomfort⁽²⁾
  • soft contact lens
  • intraocular pressure-lowering agents
• stage 4 – corneal transplantation if symptoms or vision are unacceptable⁽²⁾
  •  penetrating keratoplasty is full thickness corneal transplant, endothelial keratoplasty is replacement of posterior layer of cornea
  •  endothelial keratoplasty might have lower graft rejection rates than penetrating keratoplasty in patients with Fuchs endothelial dystrophy (level 2 [mid-level] evidence)

Medications

•  topical 5% sodium chloride solutions may be needed every 5-15 minutes in morning to clear vision⁽²⁾
• intraocular pressure-lowering agents to lower anterior chamber pressure⁽²⁾
  •  considered an option for patients with pressure within normal limits, because corneal hydration depends on endothelial pumping against anterior chamber pressure
  •  carbonic anhydrase inhibitor should be avoided because of potential interference with Na-K-ATPase pump

Surgery and Procedures

Penetrating Keratoplasty

• older donor age might not be associated with increased risk of long-term graft failure in patients with penetrating keratoplasty having corneal transplantation (level 2 [mid-level] evidence)
  •  based on randomized trial with allocation concealment not stated
  •  1,090 patients with penetrating keratoplasty having corneal transplantation were randomized to receive corneas from donors aged 12-65 years vs. corneas from donors aged 66-75 years and were followed for up to 12 years
  •  62% had Fuchs dystrophy, 34% had pseudophakic or aphakic corneal edema (PACE), and 4% had other corneal endothelial disorders
  •  median follow-up 9.7 years
  •  graft failure defined as need for regrafting procedure or cloudy cornea compromising vision for 3 consecutive months
  •  10-year graft failure rate 23% with corneas from donors aged 12-65 years vs. 29% with corneas from donors aged 66-75 years (not significant)
  •  in post hoc analysis, corneas from donors aged 12-33 years associated with significantly lower graft failure rate compared to corneas from donors ≥ 34 years old
  •  Reference – Cornea Donor Study (Ophthalmology 2013 Dec;120(12):2419full-text)
  • history of glaucoma and diagnosis of PACE each associated with increased risk of long-term graft failure after corneal transplantation in patients with penetrating keratoplasty
    •  based on cohort analysis of data from Cornea Donor Study
    •  all patients in Cornea Donor Study were included in analysis
    •  overall 10-year graft failure rate 21%
    • factors associated with increased risk of long-term graft failure included (p < 0.001 for each)
      •  prior glaucoma surgery with or without use of intraocular pressure-lowering medications
      •  diagnosis of PACE
      •  reduced endothelial cell density after transplant
      •  increased corneal thickness after transplant
    •  Reference – JAMA Ophthalmol 2015 Mar;133(3):246
• penetrating keratoplasty reported to have 64% rate of long-term corrected acuity of ≥ 20/40 (level 3 [lacking direct] evidence)
  •  based on case series
  •  retrospective chart review of 126 eyes with Fuchs dystrophy and at least 1 year of follow-up
  •  mean follow-up after transplantation 8.4 years
  •  89% (112) had graft that remained clear
  •  64% (81) had best corrected acuity 20/40 or better
  •  29% (37) had graft rejection
  •  44% (55) had subsequent cataract surgery
  •  Reference – Arch Ophthalmol 1996 Jan;114(1):15
• 85% graft survival at 5 years reported following penetrating keratoplasty (level 2 [mid-level] evidence)
  •  based on retrospective chart review of 784 penetrating keratoplasties
  • 73 patients with Fuchs dystrophy had penetrating keratoplasty
    •  90% graft survival at 3 years
    •  85% graft survival at 5 years
  •  Reference – Br J Ophthalmol 2006 Jun;90(6):728
• repeat penetrating keratoplasty associated with poor graft survival and poor visual acuity (level 2 [mid-level] evidence)
  • based on retrospective chart review of patients having repeat penetrating keratoplasty
    •  all patients had initial and repeat surgery at same institution
    •  mean follow-up 43 months
  • study included 13 eyes with Fuchs dystrophy had repeat penetrating keratoplasty
    •  3 (23%) had graft survival, 10 (77%) had graft failure
    • visual outcomes after repeat surgery
      •  0 had ≥ 20/40 acuity
      •  2 (15%) had 20/50-20/160 acuity
      •  6 (46%) had acuity between 20/200 and ability to count fingers at 20/200
      •  5 (39%) had ability to distinguish hand movement in front of face
  •  Reference – Br J Ophthalmol 2006 Mar;90(3):324full-text
• addition of cyclosporin or mycophenolate mofetil to steroids may not improve clear graft survival in patients having penetrating keratoplasty
  •  based on Cochrane review of trials with unclear allocation concealment
  •  systematic review of 6 randomized trials evaluating systemic or topical immunosuppressants in 561 patients having high- or normal-risk penetrating keratoplasty
  •  high-risk keratoplasty defined as repeat keratoplasty, graft position close to limbus, presence of 3 or 4 quadrants with deep vascularization, transplantation of highly immunogenic graft, severe atopic dermatitis, or steroid-response glaucoma
  •  4 trials compared immunosuppressant vs. placebo or no additional treatment, 2 trials compared different immunosuppressants to one another
  •  patients in both groups received systemic steroids, topical steroids, or both unless contraindicated
  •  mean duration of follow-up ranged from 6 to 34.9 months
  •  graft rejection defined as immune reaction requiring change in therapy
  • for high-risk keratoplasty
    • comparing mycophenolate mofetil (MMF) 1,000 mg twice daily for 6 months then 500 mg twice daily for 2 weeks vs. no MMF in 1 trial with 87 patients
      •  clear graft survival at 3 years in 80% vs. 75.7% (not significant)
      •  graft rejection at 3 years in 16% vs. 32.4% (no p value reported)
    •  no significant differences between groups in graft rejection (about 18% in both groups) and visual acuity at 1 year comparing cyclosporin A (CsA) 2% topically vs. placebo (frequency, duration not reported) in 1 trial with 78 patients
    •  comparing MMF 1 g twice daily vs. CsA titrated to target blood level 120-150 ng/mL for 6 months, no significant differences in clear graft survival at 3 years (92.6% with MMF, 84% with CsA), graft rejection at 3 years, or adverse events in 1 trial with 52 patients
  • comparing CsA 1%-2% topically 4-6 times daily to placebo for 6 months for graft rejection after normal-risk keratoplasty
    • no significant difference between groups in
      •  clear graft survival at 6 or 18 months (over 90% in both groups) in analysis of 2 trials with 283 patients
      •  mean best-corrected visual acuity at 18 months in 1 trial with 43 patients
    •  risk of graft rejection at 6 months 5.9% with CsA vs. 15.3% with placebo (p < 0.05, NNT 11) in 1 trial with 230 patients
  • comparing tacrolimus 0.06% topically 3 times daily vs. prednisolone acetate 1% topically (5 drops per day tapered within 6 months) for 6 months in 1 trial with 40 patients having normal-risk keratoplasty
    •  clear graft survival at 6 months 100% in both groups
    •  risk of graft rejection at 6 months 0% vs. 10% (not significant)
    •  burning sensation in 30% vs. 0% (p < 0.05, NNH 3)
  •  Reference – Cochrane Database Syst Rev 2015 Aug 27;(8):CD007603

Endothelial Keratoplasty

• Descemet’s stripping automated endothelial keratoplasty (DSAEK)
  • ultrathin DSAEK (UT-DSAEK) improves best spectacle corrected visual acuity more than standard DSAEK in patients with Fuchs dystrophy (level 1 [likely reliable] evidence)
    •  based on randomized trial
    •  66 adults (mean age 72 years) with irreversible corneal endothelial dysfunction from Fuchs dystrophy were randomized to ultrathin DSAEK vs. standard DSAEK and followed for 1 year
    •  mean donor corneal graft thickness was 101 micrometers in ultrathin DSAEK group and 209 micrometers in DSAEK group
    • mean best spectacle corrected visual acuity (BCSVA) comparing ultrathin DSAEK vs. standard DSAEK
      •  at 3 months 0.17 logarithm of minimum angle of resolution [logMAR] (20/30 snellen equivalent [SE]) vs. 0.28 logMAR (20/38 SE) (p = 0.001)
      •  at 6 months 0.14 logMAR (20/28 SE) vs. 0.24 logMAR (20/35) (p = 0.002)
      •  at 12 months 0.13 logMAR (20/27 SE) vs. 0.2 logMAR (20/32 SE) (p = 0.03)
    •  no significant differences in rates of donor perforation or graft dislocation, refractive outcomes, or endothelial cell density
    •  primary graft failure in 1 patient with ultrathin DSAEK
    •  Reference – UT-DSAEK trial (Ophthalmology 2016 Nov;123(11):2276)
  • DSAEK reported to improve average best spectacle corrected visual acuity (BSCVA) without inducing astigmatism at 6 months (level 3 [lacking direct] evidence)
    •  based on noncomparative data from prospective cohort study
    •  34 patients aged 46-97 years with Fuchs dystrophy (11), pseudophakic bullous keratopathy (22) or aphakic bullous keratopathy (1) had simple DSAEK (23) or DSAEK in combination with phacoemulsification and posterior chamber intraocular lens insertion (triple procedure) (11) and were followed for 6 months
    •  88.2% (33) had improved BSCVA overall
    •  61.8% (21) achieved BSCVA of 20/40
    • comparing 6-month postoperative outcomes vs. preoperative values
      •  mean BSCVA 20/42 vs. 20/99
      •  mean spherical equivalent refractive error 0.974 diopters vs. -0.062 diopters (p = 0.0003) (triple procedure patients not included in this outcome)
      •  mean refractive astigmatism 1.8 diopters vs. 1.68 diopters (not significant)
      •  mean endothelial cell density 1,396 vs. 2,826 in 30 eyes (p < 0.0001) (average 50.4% cell loss)
    •  no significant differences between eyes having simple DSAEK and triple procedure for 6-month postoperative BSCVA or endothelial cell density
    • adverse events included
      •  3 patients requiring repeat DSAEK
      •  1 patient acquiring pupillary block glaucoma
      •  6 acute graft rejections which were successfully treated
    •  all grafts remained clear during 6-month follow-up
    •  Reference – Cornea 2007 Jul;26(6):670
  • considerations
    • donor eye preservation time of 8-14 days might not be as effective as ≤ 7 days for graft success in patients with Fuchs endothelial corneal dystrophy having DSAEK (level 2 [mid-level] evidence)
      •  based on randomized noninferiority trial without per-protocol analysis
      • 1,151 adults (1,406 eyes) (median age 70 years, 60% women) having DSAEK for Fuchs endothelial corneal dystrophy (94%) or pseudophakic or aphakic corneal edema were randomized to receive donor corneas with 8- to 14-day preservation time (PT) vs. donor corneas with ≤ 7-day PT and followed for 3 years
        • all surgeons had previously performed ≥ 50 DSAEK cases and had primary donor failure rate < 3% and dislocation rate needing intervention < 15% in previous year
        • donor corneas met Eye Bank Association of America criteria for DSAEK
      • 1,330 eyes had surgery
      • graft failure defined as cloudy or equivocally cloudy cornea on first postoperative day without clearance at ≤ 8 weeks, clear cornea after surgery that became and remained cloudy for 90 days, or regrafting
      • noninferiority of donor corneas stored 8-14 days defined as rate of graft success at 3 years < 4% lower than corneas stored ≤ 7 days at limit of 1-sided 95% CI for difference
      • 7.6% of eyes were lost to follow-up, 100% included in analysis
      • comparing donor corneas with 8- to 14-day PT vs. ≤ 7-day PT
        • graft success in 92.1% vs. 95.3% (upper limit of 95% CI for difference 5.4% lower, noninferiority not met)
        • post hoc evaluation of postoperative positioning outcomes (p = 0.01 for overall distribution)
          • total detachment in 8% vs. 5%
          • graft repositioning without dislocation in 2% vs. 0.6%
          • interface fluid without total detachment or dislocation in 12% vs. 11%
      • 3-year graft failure by length of PT
        • rates in subgroup analyses: 3.5% with PT 0-4 days, 4.8% with PT 5-7 days, 5.9% with PT 8-11 days, and 10.2% with PT 12-14 days
        • increasing PT associated with increased graft failure (hazard ratio 1.1 per 1-day increase in PT, 95% CI 1.03-1.18)
      • Reference – CPTS trial (JAMA Ophthalmol 2017 Dec 1;135(12):1401full-text)
    • operative complications, donor diabetes, and increased donor corneal thickness may each be associated with increased risk of graft dislocation in patients with Fuchs endothelial corneal dystrophy having DSAEK
      •  based on cohort analysis of CPTS trial
      • 1,330 eyes of 1,090 patients were included in analysis
      • factors associated with increased risk of graft dislocation included
        • operative complications (adjusted odds ratio [OR] 2.97, 95% CI 1.24-7.11)
        • donor who had diabetes (adjusted OR 2.29, 95% CI 1.3-4.02)
        • increased prelamellar dissection central corneal thickness (adjusted OR 1.13 per 25 micrometers, 95% CI 1.01-1.27 increase)
      • intraocular pressure event (IOP) (> 40 mm Hg or paracentesis for pupillary block or angle closure) during first postoperative week associated with increased risk of graft failure up to 3 years (hazard ratio 3.42, 95% CI 1.01-11.53)
      • Reference – Am J Ophthalmol 2019 Jul;203:78full-text
• Descemet membrane endothelial keratoplasty (DMEK)
  • DMEK may improve best corrected visual acuity at ≥ 6 months, but may increase risk of graft dislocation compared to DSAEK in patients with Fuchs dystrophy (level 2 [mid-level] evidence)
    • based on Cochrane review of observational studies
    • systematic review of 4 observational studies comparing DMEK vs. DSAEK in 72 adults (144 eyes) with Fuchs dystrophy
    • follow-up ranged from 6 to 24 months
    • DMEK associated with
      • improved best corrected visual acuity at ≥ 6 months (mean difference 0.14 logMAR, 95% CI 0.1-0.18 logMAR) in analysis of 4 studies with 70 patients (140 eyes)
      • increased graft dislocation (risk ratio 5.4, 95% CI 1.51-19.27) in analysis of all studies
    • no severe visual loss or primary graft failure reported
    • 1 corneal graft rejection reported in DSAEK group
    • Reference – Cochrane Database Syst Rev 2018 Jun 25;(6):CD012097
  • DMEK associated with decreased graft rejection compared to Descemet stripping procedures in adults with Fuchs endothelial corneal dystrophy or pseudophakic bullous keratopathy (level 2 [mid-level] evidence)
    •  based on systematic review of mostly observational studies
    • systematic review of 49 studies (6 randomized trials, 2 nonrandomized trials, and 41 cohort studies) evaluating postoperative allograft rejection in adults (12,893 eyes) who had endothelial keratoplasty
      • 6,867 eyes had DMEK
      • 6,026 eyes had Descemet stripping procedure
        • 56.5% had Descemet stripping automated endothelial keratoplasty (DSAEK)
        • 36.2% had Descemet stripping endothelial keratoplasty (DSEK)
        • 7.3% had ultrathin DSAEK (UT-DSAEK)
    • indications of endothelial keratoplasty included Fuchs endothelial corneal dystrophy in 45 studies and pseudophakic bullous keratopathy in 39 studies
    • postoperative treatments for prevention of graft rejection included
      • standard steroids (prednisolone acetate 1% or dexamethasone 0.1%) only in 31 studies
      • standard steroids for up to 1 month followed by soft steroids (fluorometholone 0.1% or loteprednol etabonate 0.5%) in 12 studies
      • difluprednate 0.05%, betamethasone 0.1%, cyclosporine 1%, and tacrolimus in 6 studies
    • mean follow-up was 35 months (range 12-68 months)
    • overall graft rejection
      • 1.5% (95% CI 1.2%-1.8%) with DMEK in analysis of 14 studies (p < 0.001 vs. Descemet stripping procedure)
      • 5.1% (95% CI 3.9%-6.2%) with Descemet stripping procedure in analysis of 20 studies
    • graft rejection by steroid use at ≤ 1 year
      • with DMEK
        • 0.5% (95% CI 0.1%-0.9%) with standard steroid therapy for 1 year in analysis of 8 studies (not significant vs. standard steroid for ≤ 1 month followed by soft steroid therapy)
        • 0.5% (95% CI 0.1%-0.9%) with standard steroid for ≤ 1 month followed by soft steroid therapy in analysis of 7 studies
      • 2% (95% CI 0.8%-3.2%) with Descemet stripping procedure in analysis of 13 studies
    • graft rejection by steroid use at > 1 year
      • with DMEK
        • 0.1% (95% CI -0.3% to +0.1%) with continued standard steroid therapy in analysis of 3 studies (not significant vs. soft steroid therapy)
        • 0.8% (95% CI 0.1%-1.5%) with continued soft steroid in analysis of 5 studies
      • 2.8% (95% CI 1.3%-4.3%) with Descemet stripping procedure in analysis of 3 studies
    • ocular hypertension
      • 20% (95% CI 14%-26%) with standard steroid therapy in analysis of 20 studies (not significant vs. soft steroid therapy)
      • 7% (95% CI 5.2%-8.8%) with soft steroid therapy in analysis of 3 studies
    • Reference – Acta Ophthalmol 2022 Aug;100(5):e1061full-text
  • DMEK might improve best corrected visual acuity up to 12 months but may be associated with increased risk of rebubbling compared to thin DSAEK in patients with Fuchs endothelial dystrophy and bullous keratopathy (level 2 [mid-level] evidence)
    •  based on systematic review of observational studies and small randomized trials
    • systematic review of 7 studies (3 randomized trials and 4 observational studies) comparing ultrathin (graft thickness < 130 mcm) DSAEK vs. DMEK with ≥ 6 months of follow-up in patients with Fuchs endothelial dystrophy and bullous keratopathy
    • ultrathin DSAEK associated with
      • worse best corrected visual acuity at 12 months (standardized mean difference [SMD] 0.5, 95% CI 0.27-0.74) in analysis of 6 studies with 306 eyes, consistent results at 3 and 6 months in analysis of 5-6
      • decreased rebubbling (risk ratio 0.33, 95% CI 0.16-0.67) in analysis of 6 studies with 307 eyes
    • no significant differences in graft failure, graft rejection, postoperative intraocular pressure, and endothelial cell density in analysis of 4-6 studies, all confidence intervals indicate possibility of benefit or harm
    • Reference – Am J Ophthalmol 2023 Jan;245:222
  • selected trial included in systematic review above
    • DMEK might improve best spectacle-corrected visual acuity (BSCVA) but may increase adverse events compared to UT-DSAEK in adults with Fuchs endothelial corneal dystrophy and corneal endothelial dysfunction (level 2 [mid-level] evidence)
      •  based on small randomized trial with borderline statistical significance for BSCVA
      • 54 pseudophakic eyes of 54 adults (mean age 71 years) with Fuchs endothelial corneal dystrophy and corneal endothelial dysfunction were randomized to DMEK vs. UT-DSAEK and followed for 12 months
      • mean central graft thickness in UT-DSAEK group 101 micrometers
      • high-contrast BSCVA expressed in logarithm of minimum angle of resolution (logMAR) units
      • 98% had treatment and included in analysis
      • comparing DMEK vs. ultrathin DASEK
        • high-contrast BSCVA at 1 year 0.08 logMAR vs. 0.15 logMAR (p = 0.06)
        • eyes reaching 20/25 or better Snellen BSCVA at 1 year in 66% vs. 33% (p = 0.02, NNT 3)
        • eyes reaching 20/20 or better Snellen BSCVA at 1 year in 24% vs. 4% (p = 0.06)
        • total adverse events in 58.6% vs. 25% (p = 0.01, NNH 3)
          • rebubbling in 24.1% vs. 4.1% (no p value reported)
          • retransplantation in 10.3% vs. 0% (no p value reported)
          • elevated intraocular pressure in 17.2% vs. 16.7% (no p value reported)
          • cystoid macular edema in 3.4% vs. 0% (no p value reported)
      • no significant differences in BSCVA at 3 and 6 months or refractive outcomes
      • Reference – Ophthalmology 2020 Sep;127(9):1152
  • DMEK may improve visual acuity at 12 months compared to ultrathin Descemet stripping automated endothelial keratoplasty (UT-DSAEK) in adults aged 50-81 years with Fuchs endothelial dystrophy and cataract having phacoemulsification and lens implantation (level 2 [mid-level] evidence)
    •  based on randomized trial without blinding of outcome assessors
    • 72 adults (72 eyes) aged 50-81 years with Fuchs endothelial dystrophy and cataract having phacoemulsification and lens implantation were randomized to DMEK vs. UT-DSAEK and followed for 12 months
    • exclusion criteria included corneal vascularization, glaucoma, uveitis, exudative age-related macular degeneration, geographic retinal atrophy, possible vision affecting systemic disease, and prior ocular surgery or trauma
    • primary outcome was BCVA (best-corrected Early Treatment Diabetic Retinopathy Study [ETDRS] letter score) at 12 months
    • 71 patients (99%) (mean age 68 years, 68% female) completed 12-month follow-up and were included in analysis
    • at baseline, mean visual acuity was 68.2 letters
    • comparing DMEK vs. UT-DSAEK at 12 months
      • mean visual acuity 86 letters vs. 80.4 letters (mean difference 5.7 letters, 95% CI 3-8.5 letters)
      • mean contrast sensitivity 1.44 logarithms vs. 1.35 logarithms (p = 0.08)
      • mean endothelial cell density 1,401 cells/mm² vs. 1,010 cells/mm² (p = 0.03)
      • adverse events (no p values reported)
        • ≥ 1 adverse event in 56% vs. 57%
        • rebubbling in 22% vs. 14%
        • increased intraocular pressure (> 25 mm Hg) in 22% vs. 17%
        • rejection in 3% vs. 9%
    • consistent results for visual acuity at 3 and 6 months
    • no significant difference between groups in anterior corneal astigmatism at 3, 6, or 12 months
    • Reference – Br J Ophthalmol 2023 Jun 8 early online
  • DMEK might improve best spectacle-corrected visual acuity (BSCVA) at 24 months compared to microthin Descemet stripping automated endothelial keratoplasty (MT-DSAEK) in patients with Fuchs endothelial dystrophy (level 2 [mid-level] evidence)
    •  based on follow-up of small randomized trial with borderline statistical significance
    • 56 patients (56 eyes) (mean age 72 years, 59% female) with isolated Fuchs endothelial dystrophy with corneal endothelial decompensation were randomized to DMEK vs. MT-DSAEK and followed for 24 months
    • 79% had combined phacoemulsification and endothelial keratoplasty
    • primary outcome was best spectacle-corrected visual acuity (BSCVA) reported as logarithm of the minimum angle of resolution (logMAR)
    • at baseline, mean BSCVA was 0.38 logMAR in both groups
    • 100% completed 24-month follow-up and were included in analysis
    • comparing DMEK vs. MT-DSAEK at 24 months
      • mean decrease in BSCVA from baseline 0.35 logMAR vs. 0.26 logMAR (p = 0.061)
      • mean decrease in endothelial cell count from baseline 1,160 cells/mm² vs. 1,200 cells/mm² (not significant)
      • ≥ 1 complication in 29% vs. 43% (not significant)
      • graft rejection in 0% vs. 11% (no p value reported)
    • no significant difference in vision-related quality of life at 24 months
    • Reference – Cornea 2022 Dec 1;41(12):1519
  • DMEK may improve best corrected visual acuity compared to UT-DSAEK in patients with isolated endothelial dysfunction (level 2 [mid-level] evidence)
    • based on small randomized trial
    • 50 eyes of 38 patients (mean age 68 years) with isolated endothelial dysfunction from Fuchs endothelial dystrophy (96%) or pseudophakic bullous keratopathy were randomized to DMEK vs. ultrathin DSAEK and followed for 12 months
    • thickness of transplanted tissue in DMEK about 10-15 micrometers (thinner than ultrathin DSAEK)
    • primary outcome was best corrected visual acuity adjusted for acuity at baseline
    • compared to ultrathin DSAEK, DMEK associated improvement in mean best corrected visual acuity of
      • 1.5 lines at 3 months (p = 0.002)
      • 1.8 lines at 6 months (p < 0.001)
      • 1.4 lines at 12 months (p < 0.001)
    • consistent results at 6 months in unadjusted analysis
    • 16 total ocular adverse events in DMEK group vs. 9 in ultrathin DSAEK group (not significant, but trial not powered for this outcome)
    • most common adverse event with DMEK was rebubble in 24% of eyes
    • Reference – DETECT trial (Ophthalmology 2019 Jan;126(1):19)
    • DMEK associated with reduced posterior corneal higher-order aberrations compared to UT-DSAEK in secondary analysis of DETECT trial (Ophthalmology 2019 Feb 16 early online)
    • no significant difference in vision-related quality of life at 1 year comparing DMEK to UT-DSAEK in prespecified secondary analysis of DETECT trial (JAMA Ophthalmol 2019 Jul 1;137(7):747)
• deep lamellar endothelial keratoplasty (DLEK)
  • deep lamellar endothelial keratoplasty (DLEK) reported to improve refractive outcomes with minimal astigmatism (level 3 [lacking direct] evidence)
    •  based on case series
    •  98 eyes of 88 patients with corneal edema from Fuchs dystrophy and pseudophakia had DLEK and were followed for 6 months
    •  36 eyes had large-incision (9-mm scleral access) technique and 62 eyes had small-incision (5-mm scleral access) technique
    •  no surface corneal incisions or sutures needed
    • 6-month outcomes
      •  all 98 grafts clear
      •  mean best corrected visual acuity (BCVA) was 20/46 (range 20/20-20/400)
      •  average manifest refractory astigmatism 1.34 diopters, representing average change in preoperative astigmatism of 0.28 (p = 0.013)
      •  average endothelial cell density 2,140 cells/mm², representing 25% mean cell loss from preoperative donor cell measurements
    •  Reference – Ophthalmology 2005 Sep;112(9):1541
  • DLEK associated with improved best spectacle corrected visual acuity (BSCVA) but significant endothelial cell loss 1 year after surgery (level 2 [mid-level] evidence)
    •  based on prospective cohort study
    •  35 eyes of 35 patients (mean age 71 years) received DLEK with 5-mm incision for endothelial dysfunction in Fuchs dystrophy and followed for 1 year
    •  6 patients excluded from visual acuity analysis due to preexisting glaucoma or macular disease
    • mean best spectacle corrected visual acuity (BSCVA)
      •  20/200 preoperatively (range 20/70-20/800)
      •  20/80 at 3 months
      •  20/70 at 6 months
      •  20/60 at 1 year (range 20/40-20/400) (p < 0.001 vs. preoperatively)
    • comparing 1-year postoperative vs. preoperative values
      •  mean uncorrected visual acuity 20/70 (range 20/40-20/300) vs. 20/200 (range 20/70-20/800) (p < 0.001)
      •  mean endothelial cell count from donor tissue 1,595 vs. 2,904 (45% cell loss)
    • at 1 year after surgery
      •  17 (58.6%) had BSCVA ≥ 20/60
      •  10 (38%) had BSCVA ≥ 20/50
      •  5 (17%) had BSCVA of 20/40
      •  manifest refraction spherical equivalent was -0.04 diopters
      •  manifest refraction astigmatism was 1.76 diopters
    • complications included
      •  3 partially dislocated discs
      •  2 repeat grafts
      •  1 postoperative glaucoma
    •  Reference – Cornea 2007 Jun;26(5):530

Other Surgery

• injection of human corneal endothelial cells supplemented with rho-associated protein kinase inhibitor reported to increase corneal transparency and epithelial cell density at 24 weeks in adults with bullous keratopathy
  •  based on uncontrolled trial
  •  11 adults with bullous keratopathy and no detectable corneal endolthelial cells had injection of cultured corneal endothelial cells combined with rho-associated protein kinase (ROCK) inhibitor into anterior eye chamber
  •  7 adults had Fuchs dystrophy, and 4 adults had bullous keratopathy related to argon laser iridotomy, pseudoexfoliation syndrome, or intraocular surgery
  • injection preparation and procedure
    •  isolated human corneal endothelial cells from Descemet’s membrane of young deceased donor (range of age at death 7-29 years) were cultured and subcultured
    •  a few hours before cell injection, cells were recovered, suspended to obtain appropriate number and density, and supplemented with ROCK inhibitor
    •  cultured, supplemented cells were then injected into anterior chamber of patient’s treated eye following mechanical removal of abnormal extracellular matrix on Descemet’s membrane and/or degenerated corneal epithelial cells
    •  all patients were placed in prone position for 3 hours following procedure
  • at 24 weeks after cell injection
    •  100% of treated eyes (11 of 11) had restoration of corneal transparency with corneal epithelial cell density > 500 cells/mm² at central cornea (range 947-2,833 cells/mm² )
    •  91% of treated eyes (10 of 11) had corneal thickness < 630 micrometers
    •  82% of treated eyes (9 of 11) had improvement in best corrected visual acuity of ≥ 2 lines on Landolt C eye chart
  • at 2 years after cell injection
    •  100% of treated eyes maintained corneal transparency with corneal epithelial cell density > 500 cells/mm² at central cornea (range 871-2,193 cells/mm² )
    •  100% of treated eyes had intraocular pressure within normal range (1 eye had increased in intraocular pressure (to 27 mm Hg) at 8 months after cell injection, but pressure normalized after trabeculotomy without use of antiglaucoma eyedrop medication)
  •  no patients reported to have anterior uveitis, intraocular infection, or immunologic reaction following cell injection
  •  Reference – N Engl J Med 2018 Mar 15;378(11):995, commentary can be found in N Engl J Med 2018 Mar 15;378(11):1057
• triple procedure of Descemet’s stripping and automated endothelial keratoplasty (DSAEK), phacoemulsification and intraocular lens implantation associated with improvement of best spectacle-corrected visual acuity (BSCVA) in patients with Fuchs dystrophy and coexisting senile cataracts (level 2 [mid-level] evidence)
  •  based on prospective case series
  •  21 patients with coexisting visually significant immature senile cataracts and Fuchs dystrophy with guttae of Descemet’s membrane and either microcystic epithelial edema or stromal edema had phacoemulsification and intraocular lens implantation followed by DSAEK and followed for 6 months
  • comparing 6-month postoperative vision vs. preoperative vision
    •  mean BSCVA 20/34 vs. 20/68 (p < 0.0001)
    •  mean refractive astigmatism 1.56 diopters vs. 1.46 diopters (not significant)
  •  62% (13) patients were within 1 diopter and 100% within 2 diopters of emmetropia postoperatively
  •  complications included 3 graft dislocations, 3 graft rejections, and 2 pupillary block glaucomas
  •  Reference – Ophthalmology 2007 Jul;114(7):1272

• comparison of endothelial keratoplasty to penetrating keratoplasty for Fuchs endothelial dystrophy has limited evidence to guide treatment
  •  based on Cochrane review
  •  systematic review of 3 randomized trials comparing endothelial keratoplasty vs. penetrating keratoplasty in 136 patients with Fuchs endothelial dystrophy
  •  endothelial keratoplasty is replacement of posterior layer of cornea, penetrating keratoplasty is full thickness corneal transplant
  • comparing deep lamellar endothelial keratoplasty to penetrating keratoplasty
    •  no significant difference in best corrected visual acuity at 1-2 years in 2 trials with 53 patients
    •  deep lamellar endothelial keratoplasty had significantly fewer irregular astigmatisms (higher-order aberrations) at 24 months in 1 trial with 25 patients
    •  adverse events and quality of life not reported
  • comparing femtosecond laser-assisted endothelial keratoplasty to penetrating keratoplasty in 1 trial with 80 patients
    •  femtosecond laser-assisted endothelial keratoplasty had significantly poorer best-corrected visual acuity at 12 months
    •  no significant differences in primary graft failure, graft rejection, and endothelial rejection episodes
  •  Reference – Cochrane Database Syst Rev 2014 Feb 14;(2):CD008420
• improved vision-related quality of life at 3 years reported after either endothelial keratoplasty or penetrating keratoplasty in patients with Fuchs endothelial dystrophy (level 3 [lacking direct] evidence)
  •  based on case series
  •  63 patients with Fuchs endothelial dystrophy had keratoplasty (penetrating in 19%, deep lamellar endothelial in 17.5%, and Descemet stripping endothelial in 63.5%) and were followed for 3 years
  •  vision-related quality of life assessed using 25-item National Eye Institute Visual Functioning Questionnaire PDF at regular intervals over 3 years
  •  all keratoplasty types associated with significant improvement in quality of life at 6 months, with significant continued improvement between 6 months and 3 years with penetrating keratoplasty and Descemet stripping endothelial keratoplasty
  •  Descemet stripping endothelial keratoplasty associated with faster improvement in quality of life at 6 months compared to penetrating keratoplasty (p = 0.006), but no significant differences among all keratoplasty types at 3 years
  •  Reference – Ophthalmology 2014 Nov;121(11):2147

Other Management

•  hairdryer held at arm’s length may facilitate dehydration of morning edema⁽²⁾
•  loosely-fitting high water content soft contact lens may reduce irritation and alleviate discomfort for patients with stage 3 disease experiencing ruptured bullae ⁽²⁾

Follow-Up

•  following penetrating keratoplasty, visual stabilization may take 6-9 months so prescription for corrective lenses may change⁽²⁾

Complications and Prognosis

Complications

•  infection subsequent to ruptured bullae⁽²⁾
•  acute angle-closure glaucoma⁽²⁾

Prognosis

•  slowly progressive
•  keratoplasty (corneal transplant) ultimately required by most patients⁽¹⁾

Prevention and Screening

Screening

•  may be detected during routine ophthalmologic exam (slit-lamp exam)

Guidelines and Resources

Guidelines

•  no relevant guidelines for Fuchs dystrophy found 2012 Dec 5 on MEDLINE search using guidelines limiter

Review Articles

•  review can be found in Surv Ophthalmol 1993 Sep-Oct;38(2):149
•  review can be found in Cornea 1988;7(1):2
•  review of muscular dystrophy can be found in Lancet 2013 Mar 9;381(9869):845
•  review of corneal transplantation can be found in Lancet 2012 May 5;379(9827):1749
•  review of Descemet’s stripping endothelial keratoplasty can be found in Curr Opin Ophthalmol 2007 Jul;18(4):290
•  review of trends in indications for penetrating keratoplasty 1980-2001 can be found in Cornea 2005 Oct;24(7):801
•  review of cataract surgery in Fuchs dystrophy can be found in Curr Opin Ophthalmol 2005 Aug;16(4):241
•  review of molecular genetics of corneal dystrophies can be found in Am J Ophthalmol 2003 Jul;136(1):68
•  review of patient satisfaction after corneal transplantation can be found in Cornea 2001 Oct;20(7):687

MEDLINE Search

•  to search MEDLINE for (fuchs dystrophy) with targeted search (Clinical Queries), click therapy, diagnosis, or prognosis

Patient Information

•  handout from The Corneal Dystrophy Foundation

References

General References Used

1. Afshari NA, Pittard AB, Siddiqui A, Klintworth GK. Clinical study of Fuchs corneal endothelial dystrophy leading to penetrating keratoplasty: a 30-year experience. Arch Ophthalmol. 2006 Jun;124(6):777-80.
2. Borboli S, Colby K. Mechanisms of disease: Fuchs’ endothelial dystrophy. Ophthalmol Clin North Am. 2002 Mar;15(1):17-25.