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Fuchs Dystrophy was first described by the Viennese ophthalmologist Ernst Fuchs in 19101. Fuchs reported bilateral central corneal clouding and corneal oedema, mostly in elderly female patients, with no signs of corneal inflammation1. Many years on our understanding of Fuchs' dystrophy has greatly improved, with later research describing endothelial dysfunction as a cause for these presentations as well as increased thickness of Descemet's membrane3. The corneal endothelium contains Na+,K+-ATPase pumps which are responsible for the maintenance of corneal epithelial and stromal dehydration2. In Fuchs' endothelial dystrophy, there is a gradual loss of morphological and physiological characteristic properties of the corneal endothelium, resulting in endothelial cell loss and thus, corneal oedema, ocular pain and loss of visual acuity.
A 78 year old female was seen in outpatients 8 months after her optometrist referred her with bilateral cataracts.
She complained of a 4 year history of gradual progressive vision loss in both eyes.
She expressed significant concerns with her impaired vision, notably her inability to go outdoors as she was afraid of falling. She reported feeling depressed that she was unable to perform daily activities, such as making a cup of tea or ironing.
Ophthalmic history included Age Related Macular Degeneration.
Her medical history included angina and hypertension. She was also B12 deficient as a result of a past partial gastrectomy. Other surgical history included an appendicectomy and vagotomy.
She was on ferrous sulphate, multivitamin, calchichew, aspirin, atorvastatin, esomeprazole and co-codamol. She does not consume alcoholic beverages but smokes 4 a day since she was 17 (12 pack years). She is allergic to cyclizine.
Her spectacle corrected visual acuity was 2/60 (1.48 logMAR) in the right eye, with no improvement with pinhole, and 3/18 (0.78 logMAR) in the left also with no improvement with pinhole.
On examination, there was no afferent pupillary defect. Intra ocular pressures were 12 mmHg in both eyes. There was bilateral corneal oedema and the anterior chambers were noted to be both shallow. Bilateral nuclear sclerotic cataracts were present.
Specular microscopy showed cornea guttata but was unable to provide an endothelial cell count. There was no record of corneal pachymetry having been performed.
Possible differentials include Fuchsï¿½ endothelial dystrophy, posterior polymorphous dystrophy and Hassall-Henle bodies.
The patient was diagnosed with bullous keratopathy and corneal oedema secondary to Fuchs' endothelial dystrophy.
Distance correction was +0.25/+1.50 ï¿½ 143 on the right eye and +0.25/+1.00 ï¿½ 12 on the left. Preoperative biometry showed axial lengths of 20.67 mm in the right eye and 20.45 mm in the left eye. Both eyes had average K values of 7.70 mm.
In June 08 she underwent right DSEK with phacoemulsification and intraocular lens under local anaesthesia. She was discharged with prednisolone and chloramphenicol drops.
Postoperatively the patient reported continued deterioration of visual acuity in the right eye with the visual problems causing significant impairment on her quality of life. A month later, she had raised intra ocular pressure in the right eye and subsequently underwent a right peripheral iridotomy.
In December 09, her visual acuity was 6/60 (1 logMAR) in the right eye but the left eye was only able to count fingers. Consequently triple procedure (left penetrating keratoplasty with cataract extraction and intra ocular lens) was performed on the left eye under local anaesthesia on January 2010.
Postoperatively she was eating and drinking with no complaints of pain. Her visual acuity of the left eye was 6/60 (1 logMAR), intra ocular pressure was 7 mmHg, the corneal graft was clear, the anterior chamber was deep and endothelial cells were counted to be 2600 cells/mm2.
She was discharged on the second postoperative day on chloramphenicol and predisolone drops.
Fuchs' Endothelial Dystrophy
A main feature of Fuchs' endothelial dystrophy is endothelial guttata (figure 1), which describes the thickened and nodular appearance of Descemet's membrane. It is important to distinguish guttata in Fuchs' with pseudoguttata, the latter secondary to various ocular pathologies ranging from trauma to infection to thalidomide toxicity4. If all the factors for a pseudoguttata are excluded, the term corneal endothelial dystrophy is used. However, if corneal oedema is present, it is termed Fuchs' endothelial dystrophy (FED).
FED can be categorized into 4 stages3 (table 1& figure 2), these occur over a period of 10-20 years, with bilateral and mostly asymmetric corneal changes:
Stage 1: Patients are usually asymptomatic as the remaining endothelial cells are able to compensate. Nevertheless, central corneal guttata are seen biomicroscopically, as well as a thick and grey Descemet's membrane.
Stage 2: Corneal decompensation occurs, which results in a decrease in vision due to epithelial and stromal oedema. Clouding of the stromal layer and astigmatism develops, causing a reduction in visual acuity. Other symptoms include glare and seeing halos around lights5. These symptoms are particularly worse in the morning, as sleeping reduces tear evaporation6.
Stage 3: Formation of intraepithelial and subepithelial bullae occurs. These rupture, causing significant recurring pain to the patient. Corneal sensitivity is also reduced. Visual deterioration is progressive.
Stage 4: Patient no longer feels the extreme pain felt in stage 3, this is due to the development of subepithelial scar tissue which decreases bullae formation. However, visual acuity is reduced to only hand movements.
Pathophysiology of Fuchs' Dystrophy
The exact mechanism of this is not known, this is due to various studies done at the late stages of FED7, consequently there are uncertainties whether findings are secondary to dystrophic changes of the endothelium or are primary pathogenic factors of FED. Age plays a role in deteriorating endothelial cell count, as demonstrated by Roszkowska et al8 in 2004 where 204 healthy subjects were evaluated and results showed a statistically significant reduction of endothelial cell density as age increases.
The difference in regulation of apoptosis in normal and dystrophic corneas has also been theorised as an important pathogenic factor in FED. A study done by Li et al9 demonstrated, using in situ DNA fragmentation, excessive apoptosis in the epithelium, stromal and endothelial layers of cornea with FED whereas, in stark contrast, little or no apoptosis were found in healthy corneas. Further investigation on the expression of Fas, Fasl, Bcl-2 and Bax, which are all involved in inducing apoptosis, showed marked staining by immunohistology on the epithelium, stroma and endothelium in FED corneas as compared to mild or undetected staining on normal corneas. Whether or not apoptosis is a primary causative factor or secondary to endothelial defect remains to be seen.
A Serial Analysis of Gene Expression10 (SAGE) on the endothelium with FED showed a decrease in expression of genes regulating antiapoptotic cell defence, mitochondrial and pump function.
The underexpression of mitochondrial DNA may correlate with the inefficiency of the Na+,K+ ATPase pump to dehydrate the cornea. This may be due in part to compromised ATP production by decreased mitochondria resulting in such low levels that renders pump function ineffective10.
Mitochondrial DNA is also extremely sensitive to oxidative damage and oxidative stress is indicative in old age23. FED typically occurs after the 4th decade. Thus, mitochondrial DNA mutations may be a speculative pathogenesis of FED.
There is also mention of stromal keratocytes playing a role in the pathogenesis of FED9. It has been suggested that keratocytes are responsible for the maintenance of endothelial integrity, whereby secreting growth factors trigger endothelial proliferation, consequently apoptosis of keratocytes leads to degeneration of endothelial cells9.
Decemet's membrane normally consists of collagen IV, collagen VIII,laminin, fibronectin, entactin and perlecan7. In FED, collagen VIII is responsible for the thickening of Descemet's membrane due to its abnormal accumulation. It is suspected that mutations of the a2 collagen VIII (COL8A2) gene is responsible for the accumulation of collagen VIII hence resulting in apoptosis of endothelial cells7.
A study was done by Olsen11 to establish the relative prevalence of FED in people with a history of cardiovascular disease (angina pectoris, myocardial infarction, heart insufficiency). The results showed that people with Fuchs' disease had a higher incidence of cardiovascular disease in the past. Furthermore, Olsen's discussion regarding an 'interrelationship' between corneal endothelium and vascular endothelium as well as questioning whether they share the same spectrum of diseases are plausible. Nevertheless more study is required in relation to this area.
It is claimed that there is a relationship between FED and glaucoma. Brooks et al12 revealed that if there were to be such a relationship, then a significant number of corneal guttata should be a common finding in closed angle glaucoma(CAG) as well as a similarity of anterior chamber (AC) depths between FED and CAG. Their results showed that there were lower AC depths in patients with both acute and chronic CAG compared to those with FED. Furthermore, out of the 88 patients, only one had FED.
For open angle glaucoma(OAG), Buxton et al13 examined the facility of outflow of 34 eyes with FED using tonography. Results showed that 82% had an outflow that was less than 0.18. In comparison, only 2.5% of the normal population of eyes would have this reduction. In contrast, Roberts et al14 performed a similar investigation on 38 eyes and found an average facility of outflow of 0.23 with which the authors commented that it was ï¿½not statistically different from reported values for a normal populationï¿½. With these contradictory findings, doubts are cast on the association of OAG with FED.
Cataract surgery in Fuchs' endothelial dystrophy: To triple procedure or not?
In a normal corneal endothelium, cell density is approximately 2500 cells/mm2. Densities between 500-1000 cells/mm2 is the cut off point below which corneal oedema occurs with subsequent reduced visual acuity and formation of epithelial bullae7.
It is known that cataract surgery will inevitably result in loss of endothelial cells; this is due to obvious surgical trauma. The first description of the complication was in 1912, where Arnold Knapp recorded incidence of epithelial dystrophy with corneal oedema in patients post cataract surgery16.
Triple procedure typically consists of penetrating keratoplasty, cataract extraction and intraocular lens implantation. Past publications 17,18 (such as the Preferred Practice Pattern17) has indicated that for cataract surgery done alone, a corneal thickness of 0.64mm would be the threshold of which any values greater would signify a higher risk of developing further corneal decompensation,, indicating a penetrating keratoplasty at the time of the cataract surgery.
Cataract surgery done alone has its advantages. It is:
3. has less recovery time, and
4. negates the use of immunosuppressive therapy such as steroids.
Nevertheless, itï¿½s downside in patients with FED is its contribution to endothelial cell loss. A study by Giasson et al19 on corneal guttata revealed the endothelial density of 1825 cells/mm2 in people who had cataract surgery as compared to 2500 cells/mm2 in people with healthy eyes.
Even though patients undergoing triple procedure experience longer intraoperative and postoperative sessions, the benefits outweigh the disadvantages such that it only involves 1 operation, avoidance of pain associated with epithelial bullae and most importantly, a successful postoperative improvement of visual acuity in patients with FED4. Furthermore, penetrating keratoplasty alone may increase progression of underlying cataracts17.
Penetrating Keratoplasty vs. DSAEK in Fuchsï¿½ Dystrophy.
Penetrating Keratoplasty has been the treatment of choice for FED in the past. However, with the introduction of Decemet Stripping Automated Keratoplasty (DSAEK), penetrating keratoplasty is quickly being replaced.
The disadvantages of penetrating keratoplasty include astigmatism, suture related complications such as developing suture abscess, prolonged visual rehabilitation and most crucially graft rejection20. Contact lens wear for post-keratoplastic astigmatism is also a disadvantage, as well as complications associated with it, such as conjunctivitis, contact lens induced graft rejection and corneal neovascularisation21.
A recent study was done by Bahar et al22 on 12 patients who had DSAEK done on one eye and penetrating keratoplasty done on the other. Their results showed preference to DSAEK. They documented improved recovery times, a significant improvement in uncorrected and corrected visual acuity in the DSAEK operated eye as well as a bettered contrast acuity. This improvement of vision may be attributed to the evasion of high astigmatism associated with penetrating kertoplasty. Furthermore, a subjective questionnaire was given to patients which revealed that patients were more satisfied with the DSAEK operated eye, and patients themselves reported less pain in addition to enhanced vision.
One speculative reason why the patients preferred the DSAEK operation may be to do with contact lens wear for post-keratoplastic astigmatism. The patients in the study had a mean age of 73. Elderly people may not be able to tolerate contact lens wear, maybe due to poor hand coordination to remove the lens.
Fuchsï¿½ Endothelial Dystrophy is a primary disease of the corneal endothelium which commonly affects people over the age of 40. It causes a loss in endothelial cell density as well as thickening of the Descemetï¿½s membrane resulting in a gradual loss of sharpness of vision and pain due to ruptured bullous keratopathy. The aetiology of this disease is unknown and a multitude of factors have been theorised as a possible cause. Cataract surgery has been known to decrease endothelial cell count and therefore needs to be carefully considered by the ocular surgeon. A triple procedure is beneficial in this case. Newer procedures such as DSEAK are quickly replacing the conventional use of penetrating keratoplasty. This is due to the avoidance of the potential complications of penetrating keratoplasty in addition to achieving better post operative outcomes. These new developments have also reduced the need of contact lens wear subsequently steering clear of complications related to contact lens.