1.  Corneal fine needle diathermy with adjuvant bevacizumab to treat corneal neovascularization in children Asim Ali, MD, FRCSC, Uri Elbaz, MD, Carl Shen, BMSc, Kamiar Mireskandari, MBChB, FRCSEd, FRCOphth, PhD. Department of Ophthalmology and Vision Sciences, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada The authors have no financial interest to disclose

2.   To report the outcomes of corneal fine needle diathermy (FND) with adjuvant intrastromal and subconjunctival bevacizumab injection for corneal neovascularization (CN) in children. PURPOSE

3.   The medical records of all children who had undergone FND with adjuvant bevacizumab injection were reviewed retrospectively.  Treatment efficacy was evaluated by changes in visual acuity, regression of CN and clearing of lipid deposits with the aid of slit lamp colour images that were taken prior to surgical intervention and at last follow-up visit.  Postoperative complications were recorded and served to assess the safety of the procedure. METHODS

4.   The needle tip from a stainless steel needle detached from a 10-0 monofilament nylon suture was inserted intrastromally approximately 1mm from the limbus to the level of corneal new vessels.  Unipolar diathermy was then lightly tapped against the needle and served to heat the needle in its corneal track to a degree where blanching of the vessels was noticeable with minimal stromal collagen shrinkage.  An attempt was made to cannulate the vessels or at least disrupt their integrity to further enhance the thermal effect.  This was repeated as needed to disrupt all of the blood vessels.  Once cauterization was complete, bevacizumab 25 mg/ml was injected into the deep stroma (up to 2.5mg in 0.1ml per each corneal quadrant involved) in proximity to the vessels until whitening around the vessels was visible and the remainder into the subconjunctival space adjacent to areas of CN. SURGICAL TECHNIQUE

5.   Nine eyes of 9 patients were included in this study.  The mean patient age was 8.4 ± 4.2 years (4-15 years) and the mean follow-up time was 18.7 ± 12.2 months (5 – 35 months).  Following treatment, 8 out of 9 eyes treated (88.9%) had complete CN resolution with subsequent resolution of corneal edema within 1 month of treatment.  They all maintained corneas devoid of vessels throughout a mean follow-up of 17.0 ± 11.9 months (5 – 35 months) from surgery. RESULTS

6. FND – fine needle diathermy, CN – corneal neovascularization; CDVA – corrected distance visual acuity; HSK – herpes simplex keratitis; BKC – blepharokeratoconjunctivitis; DALK – deep anterior lamellar keratoplasty; NA – not applicable. Patient # 4 who had concomitant FND, bevacizumab injections and DALK was excluded from CDVA analysis. Patient demographics, preoperative findings and postoperative outcomes following fine needle diathermy combined with subconjunctival and corneal intrastromal bevacizumab injections. # Age (y) Eye Sex Follow-up (m) Preoperative diagnosis Previous FND Additional surgery Preoperative CN / Lipid regression Preop CDVA logMAR Postop CDVA logMAR) CN duration (m) prior to treatment CN Characterisics Lipid deposits 115OSF31 Corneal anesthesia post brain tumor resection Yes x1 Concomitant tarsorrhaphy and Consecutive corneal neurotization 37 Single stem Yes Complete / Complete 0.2 27OSM13HSKNoNone unkno wn Double stem Yes Complete / Complete 0.30 39OSF32 Corneal anesthesia exposure keratopathy post brain tumor resection Yes x 2 Concomitant Tarsorrhaphy 13 Double stem No Partial / NA 11

7. Patient demographics, preoperative findings and postoperative outcomes following fine needle diathermy combined with subconjunctival and corneal intrastromal bevacizumab injections – continued table from previous slide. # Age (y) Eye Sex Follow-up (m) Preoperative diagnosis Previous FND only Additional surgery Preoperative CN / Lipid regression Preop CDVA logMAR Postop CDVA logMAR CN duration (m) CN Characterisics Lipid deposits 45ODF10 Suture tract infection with CN No Concomitant repeat DALK (post DALK for HSK) 24 Single stem Yes Complete / NA (removed with DALK) NA 515ODM26HSKYes x 2No32 Double stem Yes Complete / Complete 0.80.5 65OSF11BKCNo Previous DALK for corneal scar 3 Double stem No Complete / NA 0.40.1 74ODF35 Suture tract infection with corneal melt and CN No Previous dermoid excision with lamellar keratoplasty 11 Single stem No Complete / NA 0.9 86OSM5 Idiopathic Corneal anesthesia No Concomitant tarsorrhaphy 1 Single stem No Complete/ NA 0.80.6 910ODF5HSKNo 1 Double stem Yes Complete/ Partial 0.90.7

8.  A A’ B B’ C’ 810µ 370µ 490µ C Corneal neovascularization resolution phases. Slit lamp photography (upper row) with time-matched Visante OCT (Carl Zeiss, Germany) images (lower row). A. Preoperative images showing neovascularization pattern, sectorial corneal haze (A) and localized stromal edema (A’). B. Clinical phase II. Three months post-surgery, a complete resolution of CN with more prominent lipid deposition. OCT (B’) shows significant decrease in corneal edema with more stromal hyperreflectivity corresponding to the increase in lipid deposition. C. Clinical phase III. Thirteen months post-surgery. No recurrence of CN, mild localized scar and completely resolved lipid deposits. OCT image (C’) shows reorganization of stroma with thickened posterior lamella (slowly resuming normal stromal thickness), less anterior hyperreflectivity and epithelial thickening compensating for the mild stromal loss.

9.  AB C D E Pre and post-operative images of patient # 9. A. Preoperative image. Nasal corneal neovascularization in patient with a history of herpes simplex keratitis showing 2 vessel stems crossing the corneal center with lipid deposits (white arrow) and mild temporal edema (slit view). B. Ten days post combined treatment. Cessation of blood flow and discontinuation of blood vessels tract is demonstrated. C, D, E. Three and a half months post combined treatment. Accentuation of lipid deposition (C), resolved temporal edema with minimal thinning (D, slit view) and complete CN resolution, quiet conjunctiva and moderate residual scarring (E).

10.  A B Immediate and late post-operative images of patient # 5. A. Intracorneal hemorrhage one day following surgery. B. Twenty-six months after combined treatment. Complete CN resolution with moderate residual scarring.  We selected the longer lasting stromal injection as our favoured technique in these children aiming for a one-time treatment under general anesthesia.  This was done immediately after FND treatment in order to saturate the corneal stroma and enhance bevacizumab’s duration of effect. DISCUSSION

11.   Of note, 2 of our patients with complete resolution of CN following combined treatment previously had multiple CN recurrences when FND alone was utilized.  In these patients, once bevacizumab was given by intrastromal and subconjunctival injection following FND, we did not observe CN recurrence even after extended follow up beyond 2 years.  This demonstrates the additive effect of the intrastromal bevacizumab injection specifically in children where CN likely behaves more aggressively than in adults and therefore presents with higher recurrence rates after FND alone. DISCUSSION

12.   we show that corneal FND with adjuvant intrastromal and subconjunctival bevacizumab injection is an effective method to treat corneal vascularization in the pediatric population.  We believe this technique simplifies the post- operative drop regimen by avoiding the need for prolonged bevacizumab or steroid drops or repeat anaesthesia for repeated subconjunctival injections in children. CONCLUSIONS