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Clinical Professor, Ophthalmology, Harvard Medical School, Boston, Massachusetts; Founder and President, Massachusetts Eye Research and Surgery Institute, Cambridge, Massachusetts
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The goal of this activity is to provide a comprehensive review of the most up-to-date information on the management of glaucoma, age-related macular degeneration, and cornea and external disease.
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As an organization accredited by the ACCME, Medscape, LLC requires everyone who is in a position to control the content of an education activity to disclose all relevant financial relationships with any commercial interest. The ACCME defines "relevant financial relationships" as financial relationships in any amount, occurring within the past 12 months, including financial relationships of a spouse or life partner, that could create a conflict of interest.
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Clinical Professor, Ophthalmology, Harvard Medical School, Boston, Massachusetts; Founder and President, Massachusetts Eye Research and Surgery Institute, Cambridge, Massachusetts
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The 2006 Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO) was held in Ft. Lauderdale, Florida, April 30-May 4, 2006. There were 5877 presentations, 1020 of them relevant to cornea and external disease. The general topic areas included wound healing, corneal neovascularization, infection, allergy, dry eye, dystrophies and degenerations, and corneal surgery.
MWJ Ferguson[1] addressed the matter of scar formation, with relevance to corneal pathology and to failure of glaucoma filtering surgery. He previously found that embryonic wounds heal perfectly with no scars. Experiments based on the fact that such wounds have high levels of tumor growth factor (TGF)beta3 and low levels of TGFbeta1 and TGFbeta2 showed that stimulation of cell migration by TGFbeta3 accelerated wound healing and helped organize the neodermis to a basketweave organization of extracellular matrix rather than parallel bundles of scar tissue collagen. As a result, Ferguson developed recombinant TGFbeta3 as a potential therapy for the prevention and reduction of scarring. Phase 2 trials showed that local administration of human recombinant TGFbeta3 by intradermal injection was safe and well tolerated, and resulted in a clinically significant prevention and reduction of scarring. It is hoped that novel pharmaceuticals now in phase 3 clinical trials may aid in the healing of wounds -- thus having a significant impact on corneal and glaucoma surgery.
Galantuomi and associates[2] described the effect of photodynamic therapy (PDT, nonthermal laser, 689 nm) with verteporfin on corneal neovascularization. Twenty patients received PDT 15 minutes after an intravenous infusion of verteporfin. Successful photothrombosis of corneal neovascularization was seen immediately after treatment in all patients, and regression was verified with corneal fluorescein and ICG angiography. There was partial vessel recanalization after 1 month in 12 patients. Repeat treatment resulted in complete regression of the new vessel. No relevant side effects were observed.
Similar results were also seen in a study of 27 patients by Nino and associates.[3] Six-month visual acuity (VA) improved at least 1 line in 5 patients (18.51%), and remained the same in the other 22; no patient lost VA. Total thrombosis was achieved in 14 patients (51.8%) and partial thrombosis (50% to 90% vessel thrombosis) in 9 patients (33.3%). A second session was required for 2 patients who had less than 50% thrombosis. Lumbar pain was the only adverse event (N = 2), and no changes in intraocular pressure, inflammatory signs, or loss of VA were observed.
Several preclinical studies showed promising results for a series of new therapeutic approaches. Ren and colleagues[4] demonstrated promise limiting corneal neovascularization with the use of the anti-vascular endothelial growth factor (VEGF) bevacizumab in a rat study, while a mice study[5] demonstrated efficacy for human amniotic fluid and pigment epithelium-derived factor (PEDF). In an in vitro and in vivo study, Fujita and colleagues[6] concluded that tumor necrosis factor-alpha (TNF-alpha) may help suppress corneal neovascularization. And Dietrich and associates[7] showed that it is possible to inhibit lymphangiogenesis in the cornea by alpha 5 integrin function by small molecules.
Inflammation has become an important target in the treatment of dry eye. Two studies posited that because polyunsaturated fatty acids are involved in inflammatory pathways, dietary supplements may help treat or relieve symptoms of dry eye.
Garcher and colleagues[8] examined the role of dietary n-6 and n-3 fatty acids in patients randomly assigned to a dietary supplement or placebo pills, thrice a day for 6 months. A questionnaire related to the dry eye symptoms and global discomfort was provided at every visit. Although there was a trend toward improvement in the Schirmer test, tear break-up time (BUT), fluorescein, and lissamine green stainings as well as the subjective results, the differences were not statistically significant.
Feher and associates[9] examined the efficacy of coenzyme Q10(CoQ10), omega-3 fatty acids(n-3 FA), acetyo-L-carnitine (ALC) on the symptoms of patients with dry eye disease. After 3 months, they found that a combination of n-3 FA, ALC, and CoQ10 significantly improved irritation symptoms, clinical signs, and frequency of topical treatment (P < .01), marginally improved the Schirmer's test (P < .05), but did not improve tear BUT. The addition of vitamin A palmitate to this treatment resulted in a significant improvement in both Schirmer's test and tear BUT by the end of 6 months compared with the baseline. The investigators concluded that systemic administration of selected combination of food supplements containing n-3 FA, ALC, and CoQ10 may improve dry eye symptoms in elderly patients; further improvement may be reached by addition of vitamin A.
Cordero and colleagues[10] reported on 4 highly unusual patients with severe keratitis sicca, secondary to acute or subacute dacryoadenitis, who eventually required systemic immunosuppressive therapy to prevent progression of keratopathy and permanent vision loss. Each patient was profoundly disabled by pain and photophobia (to the extent of staying in dark rooms) despite aggressive conventional therapy. All 4 patients were female with systemic autoimmune diseases: systemic lupus erythematosus and Sjogren's syndrome (n = 2), Sjogren's syndrome (n = 1), and rheumatoid arthritis and psoriasis (n = 1). Schirmer values at onset ranged from 0 to 2 mm. All had failed aggressive lubrication, topical cyclosporine, and punctal plugs, and 2 had failed serum tears and punctum hyphrecation. Immunosuppressive agents were used to control inflammation of the lacrimal glands, with methotrexate and cyclosporine A for 1 patient 1, cyclosporine A for the second, prednisone for the third, and methotrexate and infliximab for the fourth patient. Treatment with systemic immunomodulatory resulted in resolution of the acute inflammatory assault on the lacrimal glands and control of signs and symptoms in all cases. Final Schirmer values ranged from 3 to 10 mm.
Intralase lamellar cut assisted lamellar keratoplasty was evaluated in 18 eyes of 18 patients by Mosca and associates.[11] Corneal donor button diameters ranged between 8.2 and 8.7 mm (mean: 8.26 mm ± 0.26 SD), with a thickness ranging between 250 and 380 micrometers (mcm) (mean: 345 mcm ± 52.34 SD). Preoperatively, mean best corrected VA was 0.30 ± 0.27 SD. All grafts remained clear, and a normal corneal pattern topography and a normal corneal thickness were restored (mean corneal pachymetry: 565 mcm ± 27.34SD). Five months postoperatively, mean best corrected VA was 0.41 ± 0.12SD.
Endothelial replacement was evaluated by several investigators. In one prospective study,[12] 30 consecutive eyes underwent Descemet's stripping with endothelial keratoplasty or Descemet's stripping automated endothelial keratoplasty surgery for endothelial failure. The 3 steps used to prevent dislocation were (1) peripheral recipient bed scraping before donor insertion, (2) surface sweeping with compression to remove interface fluid, and (3) 10 minutes of an undisturbed anterior chamber air bubble intraoperatively. No incisions to drain interface fluid were used and a minimal residual air bubble was left behind (the patient was kept supine for 1 hour postoperatively). The authors reported that there were no donor button dislocations in this series. Both the central and peripheral interface were clear postoperatively.
Two intriguing results from stem cell research were reported. Using nestin fluorescein staining, McGowan and associates[13] reported finding evidence for stem cells, possibly capable of transdifferentiation into corneal endothelial cells, in the posterior limbus. This finding has potential implications for improved healing of the corneal endothelium after wounding. Oh and associates[14] looked at the possibility of inducing bone marrow (BM) stem cells to transdifferentiate into corneal epithelial cells. Transdifferentiation appeared to occur at 4 weeks, although there was some suggestion it may be achieved earlier as well.
Although p63 is currently (probably) the best "marker" we have for identifying corneal limbal stem cells, it is clear that p63 is not a completely reliable, unique marker for such cells. Barnard and associates[15] examined the RNA and protein expression of the various p63 isoforms in cultivated limbal epithelium produced for clinical use as autografts. The authors concluded that cultivated limbal epithelium of patients suffering from limbal stem cell deficiency induced by varying causes exhibit very similar p63 isoform expression. Constructed autologous limbal epithelial grafts also exhibited similar expression of p63 and keratin 3 immunohistochemically. Hayashi and associates[16] examined whether the cell surface marker alpha 6 integrin and CD71 can be used to select corneal epithelial progenitor/stem cells. Immunofluorescence staining revealed that alpha 6 integrin was expressed throughout by the basal epithelial cells, while CD71 was expressed abundantly in corneal epithelium, leading the authors to conclude that alpha 6 integrin and CD71 may serve as useful cell surface markers in the enrichment of corneal epithelial progenitor/stem cells.
Jansen and associates[17] reported on long-term follow-up of patients who had required penetrating keratoplasty as a consequence of corneal damage caused by recurrent herpes simplex keratitis. The investigators analyzed the long-term outcomes of patients treated chronically with oral acyclovir aimed at preventing additional episodes of viral reactivation and recurrent keratitis. During the 5-year follow-up, there were 8 recurrences in the acyclovir-treated patients and 16 in the placebo group (P = .006; unifactorial analysis of variance). The researchers reached a similar conclusion to this author's group:[18] that 2 x 400 mg acyclovir for 6 months after keratoplasty appears to be effective for prevention of recurrent herpes simplex keratitis extending to 5 years postoperatively. Our strategy has been to treat with one 800-mg capsule once daily, indefinitely; we have seen no recurrences when we use this technique.
The matter of autologous serum tear therapy for persistent corneal epithelial defects was addressed by 2 research groups. Jeng[19] performed a retrospective chart review of 12 patients during a 14-month period who underwent treatment with 50% autologous serum eyedrops every 2 hours while awake for a persistent corneal epithelial defect that was nonresponsive to conventional medical treatment. All corneas were neurotrophic, with etiologies of herpetic (5 eyes), post-keratoplasty (4 eyes), diabetic (1 eye), and unknown (2 eyes). Nine eyes (75%) healed within 4 weeks (mean, 1.8 weeks) of starting therapy. One of the 9 eyes developed a recurrence of the epithelial defect when the eyedrops were tapered to twice daily. Of the 3 eyes that did not heal completely, the epithelial defects decreased significantly in size during the treatment period. No cases of infectious keratitis occurred in any of the eyes treated.
Schrader and colleagues[20] came to the same conclusions after studying the treatment of persistent epithelial defects (PED) with autologous serum eyedrops combined with the use of a bandage contact lens (BCL) in 6 eyes (5 patients). The PEDs were due to rheumatoid sterile corneal ulcer (n = 1), neurotropic keratopathy (n = 3), or partial limbal stem cell deficiency (n = 1), and all patients had been unsuccessfully treated with conventional therapy. Serum eyedrops were applied 8 times a day. The PED healed in 5 of 6 eyes after a treatment period of 14.2 ± 8.9 days. In 1 eye, the PED became smaller, but it took 90 days until the lesion healed completely. In 3 eyes (2 patients), white deposits appeared on the surface of the BCL during the treatment after 12.3 ± 5.1 days. Because no signs of inflammation were observed and the epithelial defect improved, a new identical lens was applied and the medication continued unaltered. Examination did not indicate bacterial colonization. The authors concluded that their findings suggest that the combination of a therapeutic contact lens and serum eyedrops can be successfully used in the treatment of persistent epithelial defects. Deposition of albumin may occur on the surface of the contact lenses, which -- in the small group presented here -- caused no unwanted effects.
Supported by an independent educational grant from Genentech.
