Corneal Surgery in the Treatment of Dry Eye
Severe forms of dry eye can lead to scarring of the cornea. Persistent defects in the precorneal tear film and associated degenerations of the corneal epithelium can cause apoptosis of stromal keratocytes. There is now ample evidence for an intensive cross talk between epithelial and stromal cells in the cornea.A good example is neurotrophic keratopathy early after penetrating keratoplasty where loss of sensory innervation leads to a reduced autonomous stimulation of tear secretion. If these eyes are not lubricated sufficiently after keratoplasty, superficial stromal scarring can be observed. Luckily, these opacifications often resolve if intensive topical lubrication is initiated early enough. In case of permanent scarring, surgical treatment options come into play.

For persistent superficial stromal scarring, lamellar corneal transplantation offers a relatively safer treatment option compared to full thickness grafting. In this situation we prefer the deep anterior lamellar keratoplasty (DALK) technique initially described by Melles et al. After preparation of a scleral tunnel at the 12-o'clock position and injection of air into the anterior chamber via a paracentesis, a custom made knife is used to dissect into a deep stromal plane immediately anterior to Descemet's membrane. The depth of incision is judged by the shadow surrounding the tip of the knife. A second and then a third specialized instrument is used to dissect within that deep stromal plane all around the cornea up to the limbal border. Thereafter, air is removed from the anterior chamber and a viscoelastic material is injected into the deep stromal pocket.

A conventional trephine (e.g. Barron) is then used to trephine with a diameter of e.g. 7 mm until viscoelastic material evades from the deep stromal pocket. After a circular excision of the anterior stromal tissue, special care has to be taken to thoroughly rinse the stromal bed and remove all remaining viscoelastic material since this later can cause interface haze. Thereafter, the lamellar donor tissue is placed into the stromal bed and immediately fixed with two continuous double running 10-0 nylon sutures. The donor tissue has to be prepared prior to this step by placing a donor corneoscleral tissue upside down (epithelial side down) and punching out an equally sized circle from the corneal center. Endothelial cells are then removed using fine dry sponges. Thereafter, trypan blue is gently placed onto remaining Descemet's membrane for better visualization and Descemet's membrane is then gently removed from the underlying stroma using fine forceps. Alternatively, for very superficial stromal scars, excimer laser phototherapeutic keratectomy can be used.

In case of deep stromal scarring, conventional full thickness penetrating keratoplasty is performed. We prefer the non mechanical trephination of donor and host tissue to reduce postoperative astigmatism and improve visual results. Trephination of donor tissue is performed in an artificial anterior chamber with a defined pressure of 22 mm Hg. After placing a metallic protection mask onto the center of the cornea, the donor tissue is excised using the 193-nm excimer laser. The recipient is prepared by marking the center of the cornea using a radial keratometry marker. Then again, a metallic protection mask is placed onto the recipient and the center of the cornea is excised along the metallic mask using the excimer laser. After removal of the central host tissue, a small iridotomy is performed in the peripheral iris at 12 o'clock. Then the donor tissue is fixed in the recipient using eight interrupted 10-0 nylon cardinal sutures. Finally, a double running diagonal continuous suturing technique according to Hoffmann is used to fix the donor tissue permanently into the recipient rim. The cardinal sutures are removed and a placido ring is used to detect potential corneal astigmatism. The latter is then corrected as far as possible by manipulating the suture material.
In case of spontaneous perforation of ulcerations associated with severe forms of dry eye, e.g. in the context of chronic graft versus host disease, a penetrating keratoplasty a chaud has to be performed. To reduce corneal inflammation, we combine an amniotic membrane patch graft.

Special care has to be taken to provide sufficient lubrication of the graft after transplantation in eyes with reduced tear film. The surgical procedure itself exacerbates tear film deficiency by interrupting the sensory innervation and thereby autonomic stimulation of tear production. Sufficient lubrication of the graft after transplantation also seems to reduce the risk of corneal graft rejection. This may be due to the fact that dry eye causes ocular surface inflammation, which in turn activates antigen presenting cells and promotes graft rejection. In cases of severe dry eye, we perform a simultaneous amniotic membrane patch graft. Surgery for persistent epithelial defects itself using amniotic membrane transplantation is discussed below.

Limbal Stem Cell Surgery in the Treatment of Dry Eye
If severe forms of dry eye lead to limbal stem cell deficiency or if limbal stem cells are affected, e.g. in chemical burns causing dry eye due to meibo-mian gland deficiency together with stem cell deficiency, limbal stem cell surgery comes into play. There are several options when stem cells are deficient, unilateral and incomplete: (a) limbal autograft (from the ipsilateral or the contralateral eye) and (b) sequential keratectomy when the deficiency is localized. The latter can be combined with amniotic membrane transplantation. When unilateral stem cell deficiency is complete, tissue has to be obtained from the other healthy eye either by limbal autograft or by transplantation of ex-vivo cultivated limbal stem cells. These can be grafted on amniotic membrane or e.g. on fibrin gels. Transplantation of ex-vivo cultivated limbal stem cells has the advantage that only a small amount of healthy limbal tissue from the contralateral eye needs to be excised. In cases where bilateral stem cell deficiency occurs, stem cells have to be obtained from donor tissue, again either for ex-vivo amplification or direct surgical transplantation. In these cases, long term immunosuppression is mandatory to enable survival of grafted tissue.

Amniotic Membrane Transplantation in the Treatment of Dry Eye
Persistent epithelial defects and stromal ulcerations are a common problem in patients with severe dry eye, most commonly associated with neurotrophic keratopathy, rheumatoid diseases or chronic forms of graft-versus-host disease. Conservative measures include lubrication of the ocular surface, occlusion of the draining canaliculi, serum eyedrops and bandage contact lenses. If these measures fail, transplantation of amniotic membrane usually as a patch graft is a simple, reliable, fast and cost-effective measure to promote surface healing despite tear film deficiencies. Amniotic membrane acts in several ways to promote repair of the ocular surface. First, amniotic membrane can act as a new basement membrane for epithelial cells to grow on. Second, amniotic membrane exerts an anti-inflammatory milieu, e.g. by releasing IL-1 receptor antagonist. Thereby, inflammation of the ocular surface, which in itself causes dry eye, can be inhibited. Third, amniotic membrane contains growth factors (such as neurotropic growth factor (NGF)) which directly address the pathophysiology of dry eye in neurotrophic keratopathy.

Finally, amniotic membrane integrates into the cornea, either subepithelially, intraepithelially or intrastromally, and thereby smoothes surface defects in case of corneal ulceration. Amniotic membrane can be used in three different forms in the context of erosions and ulcerations of the cornea in severe dry eye: in case of pure epithelial defects, a patch of amniotic membrane is placed over the cornea and acts as a biologic contact lens. The size of the tissue can either be defined using conventional trephines or excised manually. The amniotic membrane is usually fixed using 10-0 nylon sutures with a bandage contact lens on top of it. In case of corneal ulcerations, one up to several layers of amniotic membrane can be placed in the ulcer. The most superficial layer is then sutured to the cornea. Both approaches can be combined in severe surface defect sandwich approach. Dry Eye Associated with Neurotrophic Keratopathy Neurotrophic keratopathy is characterized by a combination of severe to moderate dry eye with a reduced healing capacity of the corneal epithelium.

Causativ
e for a neurotrophic keratopathy is a defect in the sensory innervation of the cornea, i.e. the first branch of the trigeminal nerve. The reduced sensory information from the cornea leads to a reduced stimulation of the autonomic innervation of the basal and reflex tear production. Clinically, neurotrophic dry eye in the first stage appears as a normal keratoconjunctivitis sicca, i.e. epithelial surface irregularities, dot-like flu-orescein and rose bengal staining. Especially in the first stage of neurotrophic keratopathy it is very easy to miss the diagnosis and confuse a stage I neurotrophic keratopathy with a dry eye of other origin. Therefore, it is imperative to perform aesthesiometry of the corneal surface in all patients with unilateral or asymmetric or abnormal dry eye disease. Neurotrophic keratopathy then progresses to stage II, which is characterized by a persisting epithelial defect and may eventually lead to stage III disease, which is a corneal ulcer with the danger of progressive corneal melting and perforation. In all three stages, corneal aesthesiometry is a decisive step in making the correct diagnosis. Treatment of stage I—III primarily consists of topical unpreserved lubricants. Additional lid malpositions and other exacerbating factors should be minimized. Other treatment options in stage I and II include punctum plugs, bandage contact lenses and a temporary tarsorrhaphy.

Causal treatment options include the topical administration of NGFs or pro-NGF (currently in preclinical evaluation) which are essential for maintenance of normal epithelial wound healing, topical application of serum eyedrops (which also contain NGFs), and amniotic membrane transplantation (which also contains NGF). Amniotic membrane transplantation in neurotrophic keratopathy has two different indications with respect to the stage of neurotrophic keratopathy. In stage I (keratopathia punctate superficialis) and stage II (persisting epithelial defect), the purpose of amniotic membrane transplantation is to provide a natural bandage lens in addition to providing NGFs. This means that in stage I and stage II disease a 'patch' of amniotic membrane will be sutured onto the cornea (diameter up to 10 mm), usually with eight 10-0 nylon sutures, to keep the patch in place. Alternatively a larger patch, e.g. 16 mm, can be fixed onto the cornea and adjacent conjunctiva using eight 8-0 absorbable vicryl sutures. To provide a longer survival of the amniotic membrane on the corneal surface, we usually add a 17-mm bandage contact lens with prophylactic antibiotic topical drops on the amniotic membrane.

The strategy shifts in stage III neurotrophic keratopathy with ulceration where amniotic membrane grafts are placed in the ulcer and the most superficial layer sutured to the adjacent corneal stroma, again with usually eight 10-0 nylon sutures. In addition, one can place a patch on top of the cornea and the conjunctiva again sutured with eight single stitches with a 10-0 nylon sutures ('sandwich'). Again, a 17-mm bandage lens is added on top of this. The sutures and the bandage contact lens are left in place for 4 weeks with prophylactic topical antibiotic eyedrops and tear replacement. After 4 weeks the sutures are carefully removed without damaging the amniotic membrane. In summary, amniotic membrane transplantation either as a patch in stage I or II or as a graft (or sandwich) in stage III is a very reliable, easy to perform and helpful strategy to treat epithelial surface disorders or ulcers associated with the dry eye in neurotrophic keratopathy.

Treatment for Dry Eye Associated with Chronic Polyarthritis Chronic polyarthritis leads to several pathologies of the ocular surface. These include severe dry eye along with corneal melting and immune mediated inflammatory diseases of the sclera and the posterior pole of the eye. Amniotic membrane transplantation presents a useful adjunct treatment option for persistent epithelial defects associated with severe dry eye disease associated with chronic polyarthritis, which is resistant to topical treatment with tear replacement drops and punctum plugs, temporal tarsorrhaphy and serum eyedrops. In case of persisting epithelial defects, amniotic membrane transplantation is usually performed as patch graft as described above and prophylactic topical antibiotic applied. An additional bandage contact lens and the sutures are only carefully removed after 4 weeks. Amniotic membrane transplantation provides a useful and reliable strategy to relieve symptoms associated with epithelial defects associated with severe dry eye in patients with chronic polyarthritis.

Conclusions
To conclude: (1) severe forms of dry eye can cause persistent corneal epithelial defects, corneal ulcerations and consequently corneal scarring; (2) a very useful instrument in the surgical management of persistent epithelial defects is the transplantation of amniotic membrane (either as patch, graft or sandwich); (3) persistent corneal scars secondary to dry eye can be treated either by lamellar or - if deep in the stroma - by penetrating keratoplasty; (4) limbal stem cell transplantation offers a new opportunity to restore limbal barrier function and corneal surface integrity in diseases associated with severe dry eye and limbal stem cell deficiency (such as chemical burns), and finally (5) the possibility to transplant ex-vivo cultivated limbal stem cells on fibrin gels as carriers greatly improves the management of patients with unilateral limbal stem cell deficiency.