Adjunctive Autologous Serum Tears in High-Risk Penetrating Keratoplasty

1. Adjunctive Autologous Serum Tears in High-Risk Penetrating Keratoplasty Erich B. Groos, Jr., M.D. Cornea Consultants of Nashville The author has no financial interest in the subject matter of this poster.

2. Introduction • Penetrating keratoplasty (PK) in the setting of corneal epithelial healing abnormalities is high risk for persistent defects and infectious keratitis. • Diagnoses such as neurotrophic keratitis and limbal stem cell deficiency (LSCD) render re-epitheliazation times slow to non-existent depending on the severity of the disease. • Controlling lubrication and managing exposure to the toxic effects of lid margin bacteria and topical mediations has limited effectiveness. • Amniotic membrane transplantation and lateral tarsorrhaphy have been used previously to provide early (AMT) or ongoing (LT) protection of the epithelium during healing. • This poster displays results of the use of 20% autologous serum tears (AST) in the perioperative and ongoing management of PK in eyes with impaired corneal epithelial healing. • This study is a historical case series. • The use of autologous serum tears in this manner and setting is not an FDA-approved treatment modality.

3. Methods • A series of 10 patients were enrolled after extensive discussion of risks and benefits of surgery. Particular attention was given to the high risk nature of keratoplasty in the setting of their particular disease states. • Surgery was performed by one surgeon (EBG) using 16 interrupted 10-0 nylon sutures. Subconjunctival dexamethasone and cephazolin were used along with Healon over the graft and tobramycin/dexamethasone (Tobradex) ointment on the lids prior to patching. • On the first postoperative day, all patients (except patient #10) were started on preservative-free 20% mixtures of autologous serum, prepared by the same pharmacy (Health and Wellness Pharmacy, Nashville, TN) in a sterile and consistent manner, q2hours while awake beginning on the first postoperative day. Vials were frozen until use and discarded after 4 days of use or sooner. • Topical preservative-free dexamethasone (0.1%) was used in place of commercial steroids and initially at q2 hours while awake. • Whenever possible, topical antibiotics (Vigamox/moxifloxacin) and glaucoma medications were chosen for either reduced frequency of application or the lack of a preservative. • The patients were seen at one day, one week and then every 2-6 weeks thereafter depending on their early course, presence or absence of complications and severity of preoperative corneal condition. • Endpoints of note were intact epithelium, degree of epitheliopathy, clarity of graft and visual acuity.

4. Results-Preoperative Patient Demographics • Age: Range - 37 to 85, Average - 67.6, Median 67 years. • Sex: 4 Male/6 Female. • Diagnosis: 10/10 with impaired corneal sensation from LSCD (1), HZV (5), presumed HZV (2), and HSV (2). 5/10 with preoperative neovascularization in at least one quadrant. • Visual Acuity: Range from 20/100 to LP, with 7/10 CF or worse. • Non-healing defects: 4/10 had hx of delayed healing of epithelial defects, 2 leading to AMT transplants and one requiring AST. 2 of these were following superficial keratectomies. • Previous Perforations: 3/10 had immediate preoperative perforations (HZV, Bipolaris ulcer, serratia marcescens ulcer), and another prior to a previous graft (fusarium ulcer). • Previous surgeries: 7/10 pseudophakic at time of transplant, 2/10 with previous PK, 1/10 with 3 PK’s-DSAEK-Ahmed Implant, and 2/10 with AMT.

5. Results-Postoperative Course • Duration of Follow-up: Range from 7 to 42, Average 22.5, Median 18.5 months. • Epithelial Healing Interval Post-op: 9/10 less than a week with one less than 2 weeks. • Graft Clarity: 8/10 clear at last follow-up, 1/10 with chronic KP from uveitis (2nd PK, Fusarium, perforation) and 1/10 with vascularization and peripheral stromal scar from allograft rejection. • Epithelial Health: 9/10 with clear, smooth epithelium at last follow-up. • Visual Acuity: 7/10 BSCVA 20/40 or better. Range 20/20 to 20/200 (20/60 - only 7 months follow-up, 20/80 - 5 previous procedures and one subsequent, 20/200 - chronic uveitis secondary to perforated fusarium ulcer and one previous PK). • Adverse events: 5/10 with persistent mixed mechanism glaucoma, 5/10 with cataract extraction (2 classic triples), one reposition of lens implant, one multiple YAG removal of inflammatory membranes from IOL. • Allograft Rejections: 1/10 resolved dramatically after hospitalization for systemic steroids to treat acute bronchial asthma. • Ongoing Treatment: 7/10 require AST as of their last follow-up. 0/10 require ongoing preservative-free drops (steroids, hypotensives).

6. Case Detail - Patient #6 • 62 YO female with history of ophthalmic herpes zoster on the left in 2003. • 7/14/2008 - Visual Acuity 20/100-, corneal stromal scarring, thinning and vascularization. Decreased corneal sensation and cataract. • 10/8/2008 - PK with ECCE and IOL. Patch overnight, Healon on cornea, tobramycin dexamethasone (Tobradex) ung on lids. • 10/9/2008 - Starts AST 20% and PF dexamethasone (0.1%) q2h while awake, moxifloxacin (Vigamox) qid. • 10/16/2008 - Graft thin and clear with intact epithelium and no vortex keratopathy. • 8/18/2009 - BSCVA - 20/20. Graft thin and clear. Fluoromethalone (FML) bid, timolol hemihydrate 0.5% (Betimol) qd and AST qid. • 1/19/2010 - BSCVA 20/20. FML bid and AST qid. • 18 months follow-up. • Preop Photo Next Slide.

7. Preop Photo - Patient # 6

8. Case Detail - Patient #3 • 74 yo female with history of Fuchs’ OU presents 12/2/2002 with bullous keratopathy and KP OS, responds to topical steroids and vision improves from 20/100 to 20/70. Pertinent medical history + for polymyalgia rheumatica and on oral steroids. • 12/2003 Phaco with IOL OS uncomplicated. • 5/5/2004 OS develops geographic ulcer and melt off steroids for 4 days. • 6/1/2004 undergoes AMT multilayer inlay in 90% non-healing defect with AMT overlay as well. • 10/25/2006 undergoes PK OS with usual postoperative regimen as discussed in methods. • 10/26/2006 - 50% epithelial defect. Starts AST, Vigamox and PF dexamethasone. • 10/31/2006 - Epithelium intact • 9/15/2009 - 20/40 BSCVA, graft thin and clear. On loteprednol (Lotemax) qd because of steroid response, AST qid. • 12/10/2009 - BSCVA 20/30- on loteprednol and AST bid. • 3/4/2010 - VA drops to 20/70 because patient forgets to use AST. 1+ central PEK in the graft. Restarted AST q2h and will see again in 4/2010.

9. Case Detail - Patient #10 • 1/27/2009 - 64 YO male with long hx of HZV keratitis with neurotrophic cornea complicated with bipolaris fungal infection OS. • 3/9/2009 - Perforation despite signs of resolving infection, glued. • 4/13/2009 - Glue gone and flat AC. VA light perception with projection. • 4/15/2009 - PK OS - Postoperative voriconazole (signs of fungal elements in recipient button), PF dexamethasone (PF dex) q2h. • 4/29/2009 - Stopped voriconazole and started AST q2h, also on brimonidine/timolol (Combigan) and travaprost (Travatan Z) for elevated IOP secondary to extensive peripheral anterior synechiae (PAS). • 6/30/2009 - Stopped PF dex for difluprednate (Durezol) tid. Planning for phaco with IOL for dense cataract. AST qid. VA no better than HM despite clear graft. • 7/31/2009 - Confluent PEK inferior one third of graft. Restarted PF dex qid and D/C difluprednate. Increased AST to q2h. Azithromycin (Azasite) to lid margins qd. • 8/30/2009 - Phaco with IOL OS. PF dex and AST q2h after surgery. • 9/30/2009 - UCVA - 20/40, BSCVA - 20/40. Now on prednisolone acetate 1% (Pred Forte) instead of PF dex. Graft thin and clear. • 3/1/2010 - Same vision, graft thin and clear. Meds: AST q3h, loteprednol bid, travaprost qd, brimonidine/timolol bid. • Photos Preop on Next Slide.

10. Preop Photo - Patient #10

11. Discussion - The Problem • The general consensus is that PK in neurotrophic corneas is very high risk to the degree that many recommend no surgery unless complications dictate (perforation or near perforation) or in the case of poor vision in the fellow eye. • Previous studies have shown comparable results in HZO patients but required lateral tarsorrhaphy in many of those eyes for success. Reed and colleagues reported on 12 (10/12 grafts clear and 9/12 with vision better than 20/80, average 3 year follow-up), and Tanure and associates reviewed 15 (13/15 clear and 8/15 with VA better than 20/100, average follow-up 50 months). • The results here are comparable or better than those reported, without the use of lateral tarsorrhaphy. • Although average follow-up is shorter, 80% of grafts were clear and 90% of epithelium clear and 100% intact. 70% were 20/40 or better and 90% 20/80 or better. None of the 3 patients with vision worse than 20/40 had that attributable to corneal opacity or irregularity. • AST appears to be a valuable, if not essential adjunct to PK in these high risk eyes

12. Discussion - The Answer? • Alternatives to AST include epithelial growth factor, nerve growth factor, allogeneic serum, autologous platelet-rich plasma, umbilical cord serum and substance-p derived peptide with insulin-like growth factor 1. • None of these have the accessibility of AST for the average patient. • Despite the instability of some of the growth factors present in serum, the preparation can be frozen and maintain clinical efficacy of up to 4 months and refrigerated up to 4 days. • AST has been used for healing epithelium in a variety of settings where is has ceased to grow. • In surgical situations it has been used following vitrectomy in diabetics and post lamellar corneal surgeries. • Only one case was reported of AST use following PK by Fernando and colleagues in the setting of graft-versus-host disease. • In this series once the initial 2 cases had shown stability following keratoplasty (both had required AMT to heal non-healing defects pre-PK), the decision to offer treatment to other patient became easier.

13. Discussion - Recommendations • Use of autologous serum tears (20%, AST) and preservative-free dexamethasone is an effective strategy to avoid epithelial complications following PK in the setting of neurotrophic keratitis, HSV, HZV and mild limbal stem cell deficiency. • If the results of this series are borne out over a longer term, this approach could change basic recommendations about keratoplasty in these high risk eyes. • The success in one patient with multiple graft failures from recurrent HSV and rejection (the former preventing aggressive treatment of the latter) suggest exciting possibilities for the management of PK’s in the setting of HSV. • Despite the limitations of the study (historical, no preoperative quantification of corneal sensation, relatively short follow-up, selected patient enrollment), the results argue the value of an expanded study of the role of AST in the management of keratoplasty in general and particularly in high risk cases.

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