i-File: Fuchs Endothelial Dystrophy

Dr. Hema Joshi, MBBS, DO, DNB

A 55-year-old female presented to the Cornea clinic with gradually progressive diminution of vision in both eyes for 1 year, which was associated with intermittent photophobia and colored haloes around lights, especially on waking up in the morning. The blurry vision gradually became clearer as the day progressed.

No history of associated pain, watering, redness, itching, or discharge.

Past Ocular History:


No history of ocular trauma or surgery in the past

Past Medical History/ History of Medication:


No significant systemic history could be elicited. Patient was not on any medication. No addictions.

Family History:


No significant family history found

Review of Systems/Systemic Examination


Systemic examination was within normal limits. All vitals were within normal limits.

OCULAR EXAMINATION


Best Corrected Visual Acuity (Snellen)

Right eye (OD): 6/36

Left eye (OS): 6/12

Ocular Motility/AlignmentFull, free, and painless in all gazes

Intraocular Pressure (IOP)

OD: 16 mm of Hg

OS: 16 mm of Hg

PupilsOU Round, regular and reacting to light

Confrontation visual fields: CVF full

Slit-lamp examination:

OD

OS

Lids/lashes

Normal

Normal

Conjunctiva/sclera

Normal

Normal

Cornea

Epithelial, stromal edema, and stromal scarring noted. Numerous dark areas s/o guttae, on the central endothelium as seen by specular reflection, causing Beaten metal-like appearance (Fig. 1A)

Epithelial and mild stromal edema noted. Numerous guttae on the central endothelium as seen by specular reflection causing Beaten metal-like appearance (Fig. 1B)

Anterior chamber

Normal in depth, quiet

Normal in depth, quiet

Iris

Normal color and pattern

Normal color and pattern

Lens

Nuclear sclerosis grade II

Early nuclear sclerosis

Dilated Fundus Examination:

OD

OS

Vitreous

Clear

Clear

Disc

0.4:1, NRR healthy

0.4:1, NRR healthy

Macula

FR shining

FR shining

Vessels

Normal in calibre, AV ratio maintained

Normal in calibre, AV ratio maintained

Periphery

Normal

Normal

Fig 1A showing large central guttae on the endothelium
causing Beaten metal appearance, along with mild
subepithelial scarring
Fig 1B showing central dark areas on endothelium
also called guttae

ANCILLARY INVESTIGATIONS:


Specular microscopic examination:

Specular microscopy of the right cornea (Fig 2A) demonstrated large numbers of dark areas. Between the dark areas, the endothelial cells appeared hyper-reflective and their boundaries could not be identified. In the left cornea (Fig 2B) there were fewer dark areas and the boundaries of endothelial cells could be identified. However, the endothelial cells were increased in size and in different shapes showing polymegathism and pleomorphism.

Fig 2A shows large lakes of dark areas representing confluent guttae, the boundaries of endothelial cells are indistinct. The cell density(CD) is markedly reduced. The endothelial cells show gross polymegathism and pleomorphism.
Fig 2B shows dark areas, guttae, between well-defined endothelial cells. The CD is reduced. The endothelial cells show polymegathism and pleomorphism

Ultrasound pachymetry:

Pachymetry showed the central corneal thickness of OD 718 μm and 589 μm in OS.

Differential Diagnosis:

  • Fuch’s endothelial dystrophy
  • Herpetic stromal keratitis
  • Pseudophakic bullous keratopathy
  • Iridocorneal endothelial (ICE) dystrophy
  • Congenital hereditary endothelial dystrophy
  • Congenital stromal dystrophy
  • Posterior Polymorphic Membrane Dystrophy

Diagnosis:


Based on the typical clinical picture and specular microscopic findings, a diagnosis of OU Fuch’s endothelial corneal dystrophy (FECD) with nuclear sclerosis was made

Clinical Course of the condition:


Taking into account the symptoms, BCVA, clinical picture, and specular microscopy findings, the patient was advised OD Descemet stripping endothelial keratoplasty (DSEK) with cataract surgery and IOL implantation. OS being the better eye was managed medically with local dehydrating agents (6% NaCl ointment 3 times a day). At 6 months follow-up visit, the patient was doing well. In OD, the graft was clear (Fig 3A), the BCVA was 6/9 with -1.50D/ -2.00D @ 30. In the left eye, the cornea was clear with minimal edema (Fig 3B), the cataract had progressed to nuclear sclerosis grade II and the BCVA was 6/12 with -1.25D.

Fig 3A OD 6 months post DSEK, the graft was clear
and the patient was doing well
Fig 3B OS managed medically was doing well,
corneal edema was reduced and patient
was having minimal symptoms

DISCUSSION


Epidemiology


FECD is the most common posterior corneal dystrophy, characterized by slowly progressive dysfunction of the corneal endothelium leading to corneal oedema and reduced vision, which, if untreated eventually results in corneal blindness. Incidence is estimated at up to 4% in adult population in the world. The disease is less prevalent in individuals of brown and black races.

FECD is more common in females; the reported preponderance ranges from 2.5:1 to 3:1. FECD can be early onset, presenting in the second or third decade, and, late-onset, presenting in the sixth or seventh decade.

Etiology


Although the disease has a proven autosomal dominant inheritance pattern, sporadic cases are the most common. The ICD3 classification 2015 has categorized FCED as:

Category 1 – Gene has been identified and a specific mutation is known. Includes Early-onset FECD – mutations in COL8A2

Category 2 – Identified chromosomal loci, but the genes have not been mapped – Includes Familial FECD. Fuchs corneal dystrophy loci (FCD) 1, 2, 3, 4 have been mapped to chromosomes 13, 18, 5, 9 respectively

Category 3 – Well-defined corneal dystrophy without known chromosomal locus – Includes most of the sporadic cases

Pathophysiology


Endothelial cells are responsible for maintaining a state of stromal dehydration against the influx of aqueous from the leaky barriers between the cells. The endothelial cells contain a number of ion pumps to maintain the fluid influx and to pump out bicarbonate ions out of the stroma and into the aqueous.

In FECD there is a generalized downregulation of antioxidants and oxidative stress-related genes. The resulting oxidative stress leads to nuclear and mitochondrial DNA damage, and eventually, apoptosis.

The stressed endothelial cells deposit banded collagen fibrils and extracellular matrix in the DM, which manifests as guttae. The DM becomes thickened. The total number of endothelial cells is reduced due to apoptosis. The remaining cells become larger to compensate (polymegathism) and the hexagonality is reduced (pleomorphism). The guttae become confluent as the disease progresses.

The continued loss of endothelial cells leads to low pumping capacity and the endothelium eventually becomes incapable of maintaining corneal deturgescence, leading to stromal edema, epithelial edema, and bullae. In the advanced stage of the disease, long-standing edema and oxidative stress leads to subepithelial and stromal fibrosis and eventually opacification.

The Krachmer grading scale is sometimes used to subjectively evaluate disease progression

Grade 0 (G0) – no guttae

Grade 1 (G1) 0–12 central guttae

Grade 2 (G2) greater than 12 central nonconfluent guttae

Grade 3 (G3) 1–2 mm of confluent central guttae

Grade 4 (G4) 2–5 mm of confluent central guttae

Grade 5 (G5) greater than 5 mm of confluent central guttae or G4 with stromal or epithelial edema

Clinical Features


Symptoms:

  • None in the very early stages
  • Blurred vision more on awakening because of overnight corneal edema
  • Glare and photophobia because of corneal edema
  • Foreign body sensation due to bullae formation
  • Severe pain and watering due to denuded epithelium from ruptured epithelial bullae
  • Loss of vision in late stages

Signs:

  • Reduced corneal sensations
  • Reduced contrast sensitivity
  • Excrescences on endothelium (guttata) produce a ‘beaten metal’ like appearance in the central cornea
  • Pigment dusting on endothelium
  • Central microcystic epithelial edema
  • Stromal edema and thickening
  • Thickened Descemet’s membrane and folds
  • Bullous keratopathy
  • Subepithelial scarring and fibrosis

The stages of Fuchs Dystrophy:

Stage

Description

I

Central, but nonconfluent corneal guttae
Patient is generally asymptomatic at this stage

II

Corneal guttae coalesce together to form dark lakes
Polymegathism
Pleomorphism
The blurring of vision and photophobia

III

Epithelial and stromal edema and/or bullae
Severe pain in case of ruptured bullae

IV

Vascularized and opaque cornea
Subepithelial fibrosis

Ancillary Investigation


Slit-lamp examination:

Specular reflection using the slit lamp biomicroscope is one of the most important tools for screening patients with compromised endothelium. Specular reflections are normal light reflexes bouncing off the posterior corneal surface. It is seen by setting the slit beam arm at about 60° from the viewing arm. The beam width should be kept at about 1mm or less. The guttae are visible as dark gaps in the regular endothelial mosaic.

Another way of assessing the endothelial defects is retroillumination on slit-lamp examination. The cornea is assessed against the fundal red glow through dilated pupil. The arms are kept at a very small angle to each other. Retroillumination photography is used to document the pattern and progression of guttae over time.

Specular microscopy:

Specular microscopy shows a magnified view of the corneal endothelium. Both qualitative and quantitative evaluation of the endothelium is done, with cell density as a quantitative measure and CV and 6A showing pleomorphism and polymegathism for qualitative assessment. Guttae appear as dark round bodies with central hyperreflective areas. In FECD, numerous guttae appear, CD decreases, CV increases, and 6A progresses over time.

FECD can be divided into 5 stages based on size, shape and confluence of guttae as seen on specular microscopy.

Stage 1

Early guttae which are smaller than size of endothelial cell

Stage 2

Larger excrescence about the size of endothelial cell, surrounded by normal endothelial cells forming a rosette pattern

Stage 3

Large excrescence surrounded by abnormal pleomorphic endothelial cells. The excrescences can be rough or smooth at this stage

Stage 4

The large excrescences are coalesced at this stage. Other endothelial cells show polymegathism

Stage 5

No recognisable cell boundaries, the cells are dark with bright hyperreflective borders.

The specular microscopy is unrecordable in advanced FECD with severe corneal edema and has limited value in these cases.

Serial pachymetry

Pachymetry is the measurement of the central corneal thickness, which is increased in moderate to severe FECD owing to corneal edema. It helps in assessing the progression of disease as the cornea edema increases secondary to endothelial cell decompensation. It also helps in decision regarding cataract surgery in FECD along with specular microscopy.

Traditionally, the CD less than 1000/mm2, and pachy values of more than 640µm are taken as cut off values, which can cause corneal decompensation post-cataract surgery.

Confocal microscopy

Confocal microscopy is a particularly useful tool for patients with advanced FECD, where specular microscopy is not possible. This technique focuses the light source and the image on the same focal plane, which allows real-time, in vivo assessment of all layers of cornea. The guttae are visible as hyporeflective, dark bodies about 20-400µm in size with central hyperreflective white reflex about 50-10µm within the surrounding endothelial cell mosaic.

The advantage of confocal microscopy is that it allows the assessment of abnormalities in all corneal layers. In FECD, the changes observed are, epithelial bullae and cysts, subepithelial and anterior stromal scarring, thickened DM and the endothelial changes like pleomorphism, polymegathism and guttae.

Anterior Segment Optical Coherence Tomography (ASOCT):

ASOCT is recently being used for monitoring disease progression in FECD and for assessment of severity. The severity is predicted by corneal central-to-peripheral thickness ratio (CPTR). The CPTR at 4 mm from the centre ratio is higher in advanced than in mild to moderate disease, which again is higher than normal corneas. ASOCT can measure both the central and the peripheral corneal thickness and thus can be a useful test for FECD.

Treatment


1. Medical treatment

  • Dehydrating agents- Hypertonic saline drops and ointment
  • Antiglaucoma medication- to lower the IOP if it is more than 22 mmHg

2. Palliative treatment for ruptured bullae- Anterior stromal puncture, Bandage contact lenses, cycloplegics

In very low visual potential cases, surgical treatment for ruptured bullae is indicated - Excimer laser phototherapeutic keratectomy, Amniotic membrane grafting, Conjunctival flap

3. Surgical treatment

  • DSAEK/DSEK – The donor graft consists of endothelium, DM and a layer of stroma. A variant, ultrathin DSAEK has a minimal stromal layer and graft is just 100 μm thick.
  • DMEK- The donor graft consists of the endothelial layer and the DM.
  • PK

Surgery is indicated in cases of refractory corneal edema, subepithelial fibrosis, stromal fibrosis and decompensated cornea.

The endothelial keratoplasties are preferred over full-thickness penetrating keratoplasties wherever possible in view of excellent visual prognosis, fewer chances of rejection, and shorter course of post-operative steroids.

Full-thickness penetrating keratoplasty is indicated in advanced disease with moderate to severe fibrosis and opaque cornea.

Cataract surgery in FECD:

Conventionally cataract surgery without keratoplasty is not advised in corneas with CD less than 1000cells/mm2 and pachy values of more than 640µm as these are taken as cut-off beyond which cornea decompensates. In mild to moderate cases, cataract surgery can be done alone with due precautions to protect the endothelium from injury. In such cases, a Dispersive type OVD is used to coat the endothelium throughout the surgery. In severe cases, it is preferable to combine cataract surgery with keratoplasty to reduce further damage to the endothelium.

4. Newer modalities

  • Topical ROCK inhibitors

The use of a selective ROCK inhibitor, Y-27632, enhances endothelial cell proliferation, promoted cell adhesion to a substrate, and suppress apoptosis. Currently, two drugs, ripasudil and netarsudil are available in India.

  • DWEK or primary Descemetorhexis

Also referred to as Descemet's Stripping Only (DSO), DWEK is a newer surgical modality for some patients with Fuchs'. Patients with localized central guttae with healthy peripheral endothelium are candidates for this. A 4mm central disc of cells is stripped without placing any graft. The rationale being, the healthy endothelial cells from periphery will migrate centrally, covering the defect, and providing good quality vision. The procedure is aided by prescribing a rho kinase inhibitor (ROCK) eye drop QID postoperatively.

  • Cultured corneal endothelial cells (CEC) transplantation

In this, cultured endothelial cells are transplanted as a sheet or by injection of a cell suspension into the anterior chamber. This is still in the trial phase.

Summary

Fuch’s Corneal Endothelial Dystrophy (FCED)

Etiology:

  • Category 1- Identified gene loci and mutation- COL8A2 – Early-onset FECD
  • Category 2- Identified chromosomal loci, gene not known- Fuchs corneal dystrophy loci (FCD) 1, 2, 3, 4 have been mapped to chromosomes 13, 18, 5, 9 respectively – Familial FECD
  • Category 3- without known chromosome loci- Sporadic FECD

Signs:

  • Excrescences on DM (Guttae) causing ‘Beaten metal’ appearance
  • Epithelial and stromal edema
  • Corneal bullae and decompensation
  • Subepithelial fibrosis in late stages

Symptoms:

  • Blurred vision, worse on awakening
  • Photophobia
  • Foreign body sensation, because of bullae
  • Severe pain, when bullae rupture

Differentials:

  • Aphakic or pseudophakic bullous keratopathy
  • Congenital hereditary endothelial dystrophy (CHED)
  • Posterior polymorphous dystrophy
  • Secondary causes of endothelial dysfunction (anterior uveitis, herpes simplex keratitis, keratouveitis etc.)

Investigations:

  • Specular reflection by slit lamp reveals presence of guttae on endothelium
  • Specular microscopy for quantitative and qualitative assessment of endothelium.
  • Confocal microscopy, in cases where specular microscopy is not possible, shows guttae on DM
  • Serial pachymetry for assessing the course of disease
  • Gonioscopy and Perimetry if required

Treatment:

  • Medical management with dehydrating agents like 5% NaCl drops or 6% NaCl ointment
  • Surgical management-
  • Descemet Membrane Endothelial keratoplasty (DMEK)
  • Descemet Stripping Endothelial Keratoplasty (DSEK)
  • Penetrating keratoplasty (PK) – in advanced cases
  • Palliative treatment-
  • Anterior stromal puncture (ASP)
  • Bandage Contact lens (BCL)
  • Excimer laser phototherapeutic keratectomy
  • Amniotic membrane grafting
  • Conjunctival flap
  • Newer treatments-
  • ROCK inhibitors topically
  • Descemet stripping Without Endothelial Keratoplasty (DWEK)

References:


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  3. Elhalis H, Azizi B, Jurkunas UV. Fuchs endothelial corneal dystrophy. Ocul Surf. 2010 Oct;8(4):173-84. doi: 10.1016/s1542-0124(12)70232-x. PMID: 20964980; PMCID: PMC3061348.
  4. Zhang J, Patel DV. The pathophysiology of Fuchs' endothelial dystrophy--a review of molecular and cellular insights. Exp Eye Res. 2015 Jan;130:97-105. doi: 10.1016/j.exer.2014.10.023. Epub 2014 Nov 1. PMID: 25446318.
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  9. doi: 10.1097/ICO.0000000000001642
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  11. Nagarsheth M, Singh A, Schmotzer B, et al. Relationship Between Fuchs Endothelial Corneal Dystrophy Severity and Glaucoma and/or Ocular Hypertension.Arch Ophthalmol. 2012;130(11):1384-1388. doi:10.1001/archophthalmol.2012.1969
  12. Naoki Okumura, Shigeru Kinoshita, Noriko Koizumi,"Application of Rho Kinase Inhibitors for the Treatment of Corneal Endothelial Diseases",Journal of Ophthalmology,vol.2017,Article ID2646904,8pages,2017.https://doi.org/10.1155/2017/2646904
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Dr. Hema Joshi, MBBS, DO, DNB
Consultant, Cornea & Ocular surface, H V Desai Eye Hospital, Pune
Dr. Hema Joshi completed her MBBS from Netaji Subhash Chandra Bose Medical College, Jabalpur. She completed her Diploma in Ophthalmology from Mahatma Gandhi Memorial Medical College and Maharaja Yashwant Rao Hospital, Indore and DNB from Medical Research Foundation, Sankara Nethralaya, Chennai. She spent sometime in the Moorfields Eye Hospital, London, UK as observer. She worked as Consultant, Cataract and General Ophthalmology in Vasan Eye Care, Chennai for 2 years. She underwent fellowship training in Cornea and Ocular surface from PBMAs H V Desai eye Hospital, Pune. She is currently working as Consultant, Cataract and Cornea, in H V Desai eye hospital Pune. Her areas of special interest are ocular surface disorders and corneal infections.
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