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Descemet Stripping Endothelial Keratoplasty in Pediatric Patients with Congenital Hereditary Endothelial Dystrophy
Journal Pre-proof Descemet Stripping Endothelial Keratoplasty in Pediatric Patients with Congenital Hereditary Endothelial Dystrophy Fan Yang, Jing Hong, Gege Xiao, Yun Feng, Rongmei Peng, Minshu Wang, Hongqiang Qu PII:
S0002-9394(19)30402-7
DOI:
https://doi.org/10.1016/j.ajo.2019.08.010
Reference:
AJOPHT 11048
To appear in:
American Journal of Ophthalmology
Received Date: 25 February 2019 Revised Date:
11 June 2019
Accepted Date: 16 August 2019
Please cite this article as: Yang F, Hong J, Xiao G, Feng Y, Peng R, Wang M, Qu H, Descemet Stripping Endothelial Keratoplasty in Pediatric Patients with Congenital Hereditary Endothelial Dystrophy, American Journal of Ophthalmology (2019), doi: https://doi.org/10.1016/j.ajo.2019.08.010. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Elsevier Inc. All rights reserved.
Descemet Stripping Endothelial Keratoplasty in Pediatric Patients with Congenital Hereditary Endothelial Dystrophy Short title: Long-term Outcomes in Different Age Groups Authors: Fan Yang, Jing Hong, Gege Xiao, Yun Feng, Rongmei Peng, Minshu Wang, Hongqiang Qu Affiliation: Department of Ophthalmology, Peking University Third Hospital Beijing Key Laboratory of Restoration of Damaged Ocular Nerve, Peking University Third Hospital
Abstract Purpose: To report the long-term outcomes of Descemet stripping endothelial keratoplasty (DSEK) with suture-assisted donor lenticule insertion performed in different age groups for the pediatric patients with congenital hereditary endothelial dystrophy (CHED). Design: Retrospective case series. Methods: Pediatric patients with CHED who underwent DSEK from January 2010 to January 2016 were enrolled. Patients were divided into two groups according to their ages: the infant group and the child group. Long-term clinical outcomes and complications were compared between the two groups. Results: 30 eyes of 16 patients were included, 19 eyes (10 patients) in the child group and 11 eyes (6 patients) in the infant group. Average follow-up period was 4.08±1.90 years (ranged from 2.5 years to 8.5 years). Corneal transparency scores of the two groups on the seventh day postoperatively did not have statistic difference. Averaged postoperative best corrected visual acuity (BCVA) in the infant group (LogMAR 0.32±0.11) was better than that in the child group (LogMAR 0.54±0.20) p=0.01 . 33% cases in the child group and 86% cases in the infant group had postoperative BCVA achieved or better than LogMAR 0.4. Average endothelial cell loss in the child group was 31.21±9.17%. Lenticule detachment occurred in three cases of the child group. Conclusions: Improved visual outcomes could be achieved in infant CHED patients after DSEK, without significant rise of complication. Suture-assisted donor lenticule insertion techniques, DM stripping and postoperative sedation are advocated technical points.
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Descemet Stripping Endothelial Keratoplasty in Pediatric Patients with Congenital Hereditary Endothelial Dystrophy Short title: Long-term Outcomes in Different Age Groups
Authors: Fan Yang, Jing Hong, Gege Xiao, Yun Feng, Rongmei Peng, Minshu Wang, Hongqiang Qu Affiliation: Department of Ophthalmology, Peking University Third Hospital Beijing Key Laboratory of Restoration of Damaged Ocular Nerve, Peking University Third Hospital Address: 49# North Garden Road, Hai Dian District, Bei Jing, China
Corresponding Author: Jing Hong Affiliation: Department of Ophthalmology, Peking University Third Hospital Beijing Key Laboratory of Restoration of Damaged Ocular Nerve, Peking University Third Hospital Address: 49# North Garden Road, Hai Dian District, Bei Jing, China Postal Code: 100191 Email: [email protected] Fax: 8610-82089951 Phone: 8610-82266566
1
Introduction Congenital hereditary endothelial dysfunction (CHED), which is characterized by bilateral diffuse corneal edema, typically presents at birth or in early infancy as a common cause of childhood corneal opacification and often results in amblyopia 1,2. Histopathologically, corneal edema is attributable to abnormalities in the Descemet-endothelium complex: diffuse thickening and lamination of Descemet’s membrane (DM) and sparse and atrophic endothelial cells 3,4. Although CHED is primarily a disease of the corneal endothelium and DM, penetrating keratoplasty (PK) has been the traditional mainstay of treatment for these patients 5-7. However, PK is a challenging task in pediatric patients compared with adults. Low scleral rigidity and positive vitreous pressure offer a high risk of vision-threatening complications during surgery, such as suprachoroidal hemorrhage. Compared with adults, pediatric patients after PK always face an increased risk of infection and rejection due to frequent suture loosening, which requires early exchange or removal and subsequent general anesthesia support 7-9. Even when clear grafts are obtained, visual rehabilitation may be complicated by intractable amblyopia due to high and unpredictable astigmatism. In addition, late traumatic dehiscence in PK wounds is more common in children than in adults 10,11, given the unpredictable nature of their daily activities. For these reasons, surgery has often been avoided or delayed for as long as possible in children with CHED, which often compromises the visual development of these patients 11. Currently, targeted corneal endothelium transplantation techniques, such as Descemet stripping endothelial keratoplasty (DSEK), have been preferred over PK for endothelial dysfunctions in children because of the advantages of rapid visual recovery, stabilized refractive error, decreased likelihood of amblyopia, and decreased risk of traumatic globe rupture. Despite these advantages, there are few series describing DSEK in pediatric patients with CHED 12-14 and even fewer involving infants 15-18. This series reported the outcomes of DSEK performed in 30 phakic eyes of 16 pediatric patients with CHED in different age groups.
Materials and Methods This retrospective cohort study was approved by the Institutional Review Board of Peking University Third Hospital. The informed consents of embracing images and data in this study were received from the patients’ parents. The medical records and eye bank records of all the CHED pediatric patients who underwent DSEK performed by Professor Hong Jing at the Ophthalmology Department of Peking University Third Hospital from January 2010 to January 2016 were analyzed. Patients were divided into two groups according to their ages at the time of surgery: the infant group included patients younger than 1 year old, and the child group included patients 1 year old or older. Retrospective data collection included demographics, family histories, and past medical and ocular surgical histories. Other preoperatively recorded data included the best corrected visual acuity (BCVA) (LogMAR visual chart), intraocular pressure (IOP), slit-lamp biomicroscopy findings and endothelial density of the donor tissue. 2
Surgical Technique The main surgical steps are illustrated in Figure 1. Preparation of the Donor Tissue The donor tissues stored in McCarey Kaufman (MK) medium were obtained from the Eye Bank of Peking University Third Hospital and were evaluated for suitability for DSEK. The donor graft dissection was performed with a Moria CB microkeratome (head 350-400 µm blade depth) (Moria Surgical, Doylestown, PA) in 26 eyes and manually using a Moria ALTK artificial anterior chamber (Moria Surgical, Doylestown, PA) in 4 eyes due to the flexible characteristics of the tissues of pediatric donors younger than two years of age. The donor tissues were prepared by the surgeon immediately before surgery, and the dissected buttons were stored in MK medium during the surgical interim. Preparation of the Recipient Bed All surgeries were performed under general anesthesia. A circular mark with a diameter of 7.5 or 8.0 mm was made on the anterior corneal surface to delineate where to strip DM. A main scleral tunnel was made at the 12 o’clock position. Using Healon GV (Abbott Medical Optics, Abbott Park, Illinois, USA) to maintain the anterior chamber, scoring of DM with a reverse Terry-Sinskey hook (Bausch and Lomb Surgical, St. Louis, MO, USA) and scraping of the recipient bed with a Terry Scraper (Bausch and Lomb Surgical) were performed. All of the removed DM specimens were sent for pathological analysis. Donor Lenticule Insertion Because of the phakic status of all these patients, pilocarpine was applied preoperatively to protect the transparent crystalline lenses, and the donor lenticule was inserted into the anterior chamber using a suture-assisted donor lenticule insertion technique 19-21 to minimize manipulations in the anterior chamber. The donor lenticule overlying a bed of cohesive viscoelastic was carefully folded and pulled into Busin’s glide (Moria Inc. Doylestown, PA, US) with forceps, and a 10-0 prolene suture was fixed at the 6 o’clock position as anchoring stitch. The anchoring stitch was tied to create a loop, after which it was placed in the anterior chamber and pulled through the incision in the 6 o’clock direction with a hook. After evacuation of all the viscoelastic material, an anterior chamber maintainer was inserted through the temporal incision to provide irrigation. The donor lenticule was pulled into the anterior chamber through the main scleral tunnel at the 12 o’clock position with the assistant of Busin’s glide and the anchoring stitch. Once inserted, the donor lenticule was unfolded in balanced salt solution (BSS, Alcon, Fort Worth, TX, USA). To prevent postoperative pupillary block by air bubbles, peripheral iridectomy was performed. Then, the scleral incision was interrupted sutured with 10-0 prolene sutures. The anchoring stitch was cut after the donor lenticule was positioned and centered. A complete air fill was performed and maintained for 10 minutes, followed by gentle partial release of air to maintain 75% air volume in the anterior chamber. The patient was maintained in the supine position for four hours. For children who could not cooperate, postoperative sedation was provided by an anesthesiologist. Postoperative Management 3
Postoperatively, topical drops including 1% prednisolone acetate, tobramycin (Tobrex, Alcon Laboratories, Inc., Fort Worth, TX), cyclosporin (1%, North China Pharmaceutical Company, Ltd., Shijiazhuang, Hebei Province, China) and artificial tears four times daily were prescribed for the first week. The dosages were reduced gradually as clinically indicated and stopped 12 months after surgery. Patients were reviewed at 1, 3, 7, and 30 days and 3, 6, and 12 months postoperatively and once per year thereafter. BCVA was tested at each visit using a LogMAR visual chart. For patients who were too young to cooperate for the vison test, whether they could fix and follow (FF) light was checked using a torch. IOP (noncontact tonometer), lenticule status, corneal clarity, and complications were recorded at each visit. Anterior segment optical coherence tomography (AS-OCT, Carl Zeiss Meditec, Dublin, CA) and endothelial evaluation with confocal microscopy (HRT-RCM, Heidelberg Engineering, GmBH, Dossenheim, Germany) were performed when possible and appropriate. Sutures were removed within the first month postoperatively. All of these patients were referred to a pediatric ophthalmologist for amblyopia therapy one month after DSEK. Statistics Postoperative corneal transparency was scored according to slit-lamp photos taken on the 7th day postoperatively compared with preoperative photos. The criterion of corneal transparency scores (CTS) were as follows: -1, worse than preoperative transparency; 0, the same as preoperative transparency; +1, better than preoperative transparency but not completely transparent 1; and +2, transparent. Differences in postoperative corneal transparency between the two groups were compared with the Mann-Whitney rank-sum test. The differences in BCVA between the two groups were compared with independent samples t-tests. Patients in the child group whose pre-operation and post-operation BCVA were both available were compared with paired samples t-test. Histopathology of Removed DM Specimens To assess the pathologic features of DM and the endothelium in CHED, histopathologic procedures were performed in all the removed DM specimens, including hematoxylin-eosin and periodic acid-Schiff staining. Then, the samples were observed by light microscopy (Cytation5, BioTek, Winooski, VT, USA, original magnification ×100). One of the removed DM specimens was further inspected using scanning electron microscopy. The sample was fixed with 2% glutaraldehyde in an 80 mM sodium cacodylate buffer (pH 7.2–7.4, 320–340 mOsm/kg), processed with gold-coated magnetic particles for solid-phase immunoassays and, after the critical point of drying, examined with a scanning electron microscope (JEOL JSM-7000F, JEOL, Peabody, USA). The sample was screened at low magnification (original magnification ×30–×200) and pictured at higher magnifications (original magnification×60.000).
Results Pre-operation and post-operation clinical data of the CHED patients in this study was listed in Table 1. 4
Thirty eyes of 16 pediatric patients were included in this study, including 9 boys and 7 girls aged from 6 months to 13 years old (average, 4.35±4.03 years old). There were 10 patients (19 eyes) in the child group with an average age of 6.50±3.66 years old and 6 patients (11 eyes) in the infant group with an average age of 0.78±0.18 years old. The average follow-up period was 4.08±1.90 years (ranging from 2.5 years to 8.5 years). In the child group, one child had a positive family history of an affected brother, two children had a surgical history of trabeculectomy, one child had a surgical history of PK in the contralateral eye, and two children had disease complicated by nystagmus. The preoperative visual acuity in the child group ranged from FF to LogMAR 1.0, and the average visual acuity was LogMAR 1.03±0.25 (n=11, excluding patients who were unable to cooperate). No family history or surgical history was reported in the infant group, and the preoperative vision test was no FF in all infant eyes. All patients in the two groups had diffuse, bilateral corneal edema, clear crystalline lenses, normal IOP and corneal diameter. The clinical diagnosis of CHED was further confirmed by histopathologic analysis of the removed DM specimens showing marked thickening and lamination of DM and an absence of endothelial cells. The scanning electron microscope images showed no endothelial cells on either side of the removed DM. The surgical procedures were smooth, and crystalline lenses were reserved in all the cases. Lenticule detachment occurred in three eyes in the child group within the first 24 hours after surgery. Two eyes were managed successfully by rebubbling, but it was difficult to reposition the lenticule in the other eye. After several times to reposition, detachment always recurred at the second day after repositioning, at last PK was performed for this eye at request of parents one month after DSEK. All other lenticules remained well attached, as confirmed by anterior segment OCT. No other surgical complications, such as pupillary block, acute cataract formation or primary graft failure, were observed. Corneal transparency began to improve within the first week after surgery and continued to improve for almost one year, presenting that the younger the age, the faster the recovery of corneal transparency (Figure2). However, CTS was12.26 in the child group (n=17) and 15.83 in the infant group (n=9) at the 7th day postoperatively, with no difference in statistic (p=0.21, two eyes in each group were excluded because of failure to take photos at the follow-up day). Vision acuity improved rapidly with corneal transparency after surgery. All patients in the infant group could achieve FF as early as the first week after DSEK, whereas no patient could do that preoperatively. All patients in the child group and four patients in the infant group were already able to cooperate in visual acuity testing with a visual chart before the last review. The average BCVA in the infant group (LogMAR 0.32±0.11) was statistically better than that in the child group (LogMAR 0.54±0.20) (p=0.01) (Table 2). The postoperative BCVA of 6 eyes (33%) in the child group and 6 eyes (86%) in the infant group had achieved LogMAR 0.4 or better at the last follow-up (Table 1). The average BCVA in the child group improved from LogMAR 1.03 preoperatively to LogMAR 0.54 postoperatively (Table 2).Patients in the child group whose pre-operation and post-operation BCVA were both available were compared, with the result LogMAR 1.03±0.25 preoperative improved to LogMAR 0.6±0.21postoperative (Table 3). Two patients in the child group in this series underwent DSEK in one eye and PK in the contralateral 5
eye. Both patients obtained better BCVA in DSEK eyes, although corneal transparency in the DSEK eye never reached the quality of the PK eye due to residual stromal haze. Endothelial cell density was evaluated with confocal microscopy in 8 patients (14 eyes, excluding the patients who could not cooperate or converted to PK) in the child group (Table 1). The average endothelial cell loss (ECL) in the child group was 31.21±9.17% at the most recent review. All patients in the infant group were still too young to cooperate for this examination. There were no signs of endothelial rejection or graft dysfunction in any of the eyes in the two groups until the final visit.
Discussion DSEK offers several advantages over PK for pediatric patients with CHED. This technique is performed under “closed system” conditions; therefore, the risk of surgical complications accompanied by low IOP can be minimized. The small corneal incision required for DSEK is unlikely to dehisce due to trauma. Few sutures and early suture removal may help to reduce the endothelial rejection rate and suture-related infections. Rapid recovery and mild astigmatism facilitate visual rehabilitation and treatment of amblyopia. However, until recently, no definitive evidence of the appropriate timing for DSEK in pediatric patients with CHED has been determined, as the profit of early visual rehabilitation must be weighed against the increased risk of surgical complications in children. Although some series with a small sample size 12-18 and isolated case reports 22-26 have reported DSEK in CHED children, no study has ever compared DSEK outcomes between different age groups among pediatric CHED patients. To the best of our knowledge, until now, this series had the largest sample size and the longest observation period for evaluating DSEK performed in CHED children and for comparing infant patients and older pediatric CHED patients. The visual outcomes of this case series were encouraging. Vision acuity improved rapidly with corneal transparency after surgery. The average BCVA was LogMAR 0.32 in the infant group and LogMAR 0.54 in the child group. The postoperative BCVA in 33% of eyes in the child group and 86% of eyes in the infant group had achieved than LogMAR 0.4 or better. Patients in the infant group had statistically better results in terms of postoperative BCVA than those in the child group, which may be due to relieving form deprivation and beginning amblyopia treatment at a younger age. In previous reports, the visual outcomes of CHED children were varied. In a report by Busin and colleagues 15, who recruited pediatric patients and adult patients, 8 of 9 eyes achieved a BCVA of 20/40 or better. In the report by Silvana and colleagues 18, which included pediatric patients with various indications, the BCVA was better than 20/40 in 8 of the 13 eyes. Sporadic case reports also presented varying BCVAs: 20/100 for a 19-year-old patient 27 and 20/50 for an 8-year-old girl 25. Regarding infant patients, Lenhart and colleagues 16 reported that an 8-month-old CHED patient had an uncorrected visual acuity of 20/40 at 24 months' follow-up after DSAEK. The wide variations in these reports might be due to different baseline conditions and different surgeons. Besides, the patient’s age was another undeniable important influencing factor. This study confirmed that good visual outcomes could be achieved after DSEK in infant CHED patients with the assistance of timely amblyopia treatment, while it was not so 6
satisfactory in older children. Worse postoperative visual acuity in the child group compared with the infant group in this series could reflect from one aspect the influence of amblyopia on older children with CHED. Although the optimal age for DSEK remains controversial, early surgical intervention should be advocated in the view of avoiding amblyopia. In this series, two patients in the child group underwent DSEK in one eye and PK in the contralateral eye. Although corneal transparency in the DSEK eye never reached the quality of PK eye due to residual stromal haze, both patients obtained better BCVA in the DSEK-treated eyes compared with the PK-treated eyes, and they both preferred the visual quality of the former. Early visual stabilization and the predictable nature of refraction error might offer more advantages in terms of amblyopia management in DSEK-treated eyes. The anatomical outcome of improvement in corneal transparency in this series was similar to that in previous reports about DSEK in CHED 12,18,27. Corneal clarity began to improve within the first week after surgery and continued to improve for almost one year. Patients in the infant group seemed to have faster recovery of corneal transparency than those in the child group, although the rough comparison of corneal transparency recovery and the small number of cases in this series prevented determining a quantitative difference in terms of statistics (p=0.21, Figure 2,). The recovery rate of corneal transparency might be related to the duration of corneal stromal edema, which is requires further observation and more cases to confirm. While early surgical intervention is advocated in children to avoid amblyopia, technical problems are challenges to be overcome to improve the safety of DSEK. The presence of a clear crystalline lens with normal accommodative function and a relatively smaller anterior chamber provides challenges to performing the operation of DSEK in the pediatric age group. Crystalline lenses were successfully reserved in all the cases in the two groups in this series. It is extremely important to protect the transparent lens in the limited manipulation space during surgery; therefore, DSEK with a suture-assisted donor lenticule insertion technique was advocated, which minimized the necessity for surgical instruments to enter the anterior chamber 20-22. The donor lenticule was pulled into the anterior chamber with an anchoring stitch, with no instrument reaching the pupil area during delivery, which reduced the risk of accidental lens damage. The suture-assisted donor lenticule insertion technique could also help to shorten the main incision because Busin’s glide did not enter the anterior chamber. The incision with a diameter of 3.5 mm used in this series was smaller than that used in previous reports 13,14 about DSEK for CHED in children, and this smaller incision may benefit patients with milder astigmatism and be less likely to dehisce due to trauma. The inability to identify or strip DM in infants < 12 months of age is another technical challenge that has been previously proposed 12,14,15,17,26, because DM in infants appears much thinner than in adults or older children. Due to poor visualization as a consequence of severe corneal edema, endothelial keratoplasty without DM stripping has been advocated for infants in some studies 12,14,15,17,26 . Busin and colleagues 15 described their experience of performing non-DM stripping endothelial keratoplasty in CHED. The authors left DM intact without removal in infants in whom DM was not visualized. However, of these six eyes, four developed lenticular dislocation on the 2nd postoperative day. Therefore, the role of this modified procedure has still been debated 7
13,27
. In this series, although DM was hardly visible and appeared firmly adherent to the underlying stroma, stripping DM was successful in all infant patients after considerable effort. Subsequent pathology examinations revealed remarkable thickening and lamination of the DM and the absence of endothelial cells. Reservation of an abnormal DM during endothelial keratoplasty is an unpredictable factor for the survival of graft endothelium cells, and the fate of donor lenticule is under a constant threat of dislocation in the future because the retained DM has been found to be a significant cause of graft detachment 28,29. Hence, the authors do not advocate for endothelial keratoplasty without DM stripping in infant patients. Graft detachment occurred in three eyes in the child group due to eye rubbing and inability to maintain in the supine position, while no graft detachment occurred in the infant group. Two eyes were repositioned successfully, however, detachment always recurred at the second day after repositioning for the other eye, and PK had to be performed ultimately. The difference in graft detachment rates between the two groups might be explained by the learning curve because all the three graft detachment cases in the child group occurred during the initial stage of this series, and not a single infant patient had undergone surgery at that time. Due to the problems that arose during the early stages, postoperative sedation was provided to babies and young children, which was very helpful. This method was believed to benefit patients who could not maintain body position during the crucial early postoperative period. The rate of graft detachment in this series was 3/30, which was much lower than that in the report by Ashar et al. 12 (2/5) involving deep lamellar endothelial keratoplasty cases and than that in the report by Busin et al. 15 (4/11) involving phakic children with CHED. This difference may be due to the lack of DM stripping in some of the cases in the abovementioned studies; however, it is certainly difficult to compare trials directly, given the differences in patient ages, disease conditions and surgical complications. Four pediatric donor tissues were used in this series, and graft detachment never occurred. Although it was difficult to manipulate and rolling edge deformity was inevitable due to the elastic nature of grafts, the obvious advantage was that grafts offered adequate and high-quality endothelial cells for young patients. Dissection of pediatric donor tissues should be performed manually because of their soft nature. Predictable graft curling and contracture of these infant donor tissue were observed during the first month after surgery and tended to be stable at the third month after surgery, which was consistent with previous experience30. Endothelial rejection or graft dysfunction never occurred in any eye in this series until the final visit. The averaged ECL in the child group was 31.21%, similar to the outcome of 30.0% from the report by Busin et al. 15 and the outcome of 35% from the report by Madi et al. 18. However, ECL was only evaluated in the child group, while all patients in the infant group were still too young to cooperate; thus, it was impossible to compare the two groups, and a longer observation period is necessary to evaluate this aspect. Based on our experience, DSEK could be a good alternative to conventional PK in pediatric patients with CHED. Good visual outcomes can be achieved in infant CHED patients after DSEK, without a significant increase in complication rates, which provides a good opportunity for subsequent visual reconstruction and amblyopia training. Suture-assisted donor lenticule 8
insertion techniques, DM stripping and postoperative sedation are advocated technical points for this population. However, further studies are required; in particular, long-term results from a larger population of DSEK patients are needed.
Acknowledgements This study is supported by National Natural Science Foundation of China (NO.31271045). No financial relationship needs to disclose in this study. Acknowledgement belongs to Miss Pei Zhang and Miss Lixue Shuai for assistance with images collection.
References 1. Thore Schmedt, Mariana Mazzini Silva, Alireza Ziaei, Ula Jurkunas. Molecular Bases of Corneal Endothelial Dystrophies. Exp Eye Res. 2012; 95(1): 24–34. 2. Weiss JS, Møller HU, Lisch W, et al. The IC3D classification of the corneal dystrophies. Cornea 2008;27(suppl 2):S1-S83. 3. Kenyon KR, Antine B. The pathogenesis of congenital hereditary endothelial dystrophy of the cornea. Am J Ophthalmol. 1971;72(4):787–795. 4. Kirkness CM, Mc CartneyA, Rice NS, Garner A, Steele A D. Congenital hereditary corneal edema of Maumenee: its clinical features, management, and pathology. Br J Ophthalmol.1987;71(2):130–144. 5. Graham MA, Azar NF, Dana MR. Visual rehabilitation in children with congenital hereditary endothelial dystrophy. Int Ophthalmol Clin. 2001;41(4):9–18. 6. Javadi MA, Baradaran-Rafii AR, Zamani M et al, Penetrating keratoplasty in young children with congenital hereditary endothelial dystrophy. Cornea. 2003;22(5):420–423. 7. Al-Ghamdi A, Al-Rajhi A, Wagoner MD. Primary pediatric keratoplasty: indications, graft survival, and visual outcome. J AAPOS. 2007;11(1):41–47. 8. Wagoner MD, Al-Ghamdi AH, Al-Rajhi AA. Bacterial keratitis after primary pediatric penetrating keratoplasty. Am J Ophthalmol. 2007;143(6):1045–1047. 9. Huang PT. Penetrating keratoplasty in infants and children. J AAPOS. 2007;11(1):5–6. 10. Williams MA, Gawley SD, Jackson AJ, Frazer DG. Traumatic graft dehiscence after penetrating keratoplasty. Ophthalmology. 2008;115(2):276–278. 11. Vanathi M, Panda A, Vengayil S, Chaudhuri Z, Dada T. Pediatric keratoplasty. Surv Ophthalmol. 2009;54(2):245–271. 12. Ashar JN, Ramappa M, Vaddavalli PK. Paired-eye comparison of Descemet’s stripping endothelial keratoplasty and penetrating keratoplasty in children with congenital hereditary endothelial dystrophy. Br J Ophthalmol. 2013;97(10):1247–1249. 13. Ashar JN, Latha M, Vaddavalli PK. Descemet's stripping endothelial keratoplasty (DSEK) for children with congenital hereditary endothelial dystrophy: surgical challenges and 1-year outcomes. Graefes Arch Clin Exp Ophthalmol. 2012;250(9):1341-1345. 14. Ashar JN, Ramappa M, Chaurasia S. Endothelial keratoplasty without Descemet's stripping in congenital hereditary endothelial dystrophy. J AAPOS. 2013;17(1):22-24. 15. Busin M, Beltz J, Scorcia V. Descemet-stripping automated endothelial keratoplasty for congenital hereditary endothelial dystrophy. Arch Ophthalmol. 2011;129(9):1140-1146. 9
16. Lenhart PD, Evans CT, Beck AD, Lee WB. Visual outcome after Descemet’s stripping automated endothelial keratoplasty in an 8-month old with congenital hereditary endothelial dystrophy. J AAPOS.2013;17(6):637-639. 17. Bellucci R, Chierego C, Bellucci C. Endothelial keratoplasty in a newborn baby with CHED. Cornea. 2011;30(12):1488-1490. 18. Madi S, Santorum P, Busin M. Descemet stripping automated endothelial keratoplasty in pediatric age group. Saudi Journal of Ophthalmology. 2012;26(3):309–313. 19. Macsai MS, Kara-Jose AC. Suture technique for Descemet stripping and endothelial keratoplasty. Cornea. 2007;26(9):1123–1126. 20. Kaiserman I, Bahar I, McAllum P, Slomovic AR, Rootman DS. Suture assisted vs forceps-assisted insertion of the donor lenticula during Descemet stripping automated endothelial keratoplasty. Am J Ophthalmol. 2008;145(6):986–990. 21. Sarnicola V, Toro P. Descemet-stripping automated endothelial keratoplasty by using suture for donor insertion. Cornea. 2008;27(7):825–829. 22. Fernandez MM, Buckley EG, Afshari NA. Descemet stripping automated endothelial keratoplasty in a child. J AAPOS. 2008;12(3):314–316. 23. Jeng BH, Marcotty A, Traboulsi EI. Descemet stripping automated endothelial keratoplasty in a 2-year-old child. J AAPOS. 2008;12(3):317–318. 24. Pineda R, Jain V, Shome D, Hunter DC, Natarajan S. Descemet's stripping endothelial keratoplasty: is it an option for congenital hereditary endothelial dystrophy? Int Ophthalmol. 2010;30(3):307–310. 25. Goshe JM, Li JY, Terry MA. Successful Descemet's stripping automated endothelial keratoplasty for congenital hereditary endothelial dystrophy in a pediatric patient. Int Ophthalmol. 2012;32(1):61-66. 26. Anwar HM, El Danasoury A, Hashem A. Descemet’s stripping automated endothelial keratoplasty for congenital hereditary endothelial dystrophy. Clin Ophthalmol. 2012;6:159-163. 27. Mittal V1, Mittal R, Sangwan VS. Successful Descemet stripping endothelial keratoplasty in congenital hereditary endothelial dystrophy. Cornea. 2011;30(3):354-356. 28. Suh LH, Dawson DG, Mutapcic L, et al. Histopathologic examination of failed grafts in Descemet’s stripping with automated endothelial keratoplasty. Ophthalmology. 2009;116(4):603–608. 29. Shulman J, Kropinak M, Ritterband DC, et al. Failed Descemet-stripping automated endothelial keratoplasty grafts: a clinicopathologic analysis. Am J Ophthalmol. 2009;148(5):752–759. 30. Rongmei Peng, Yuxin Guo, Yuan Qiu, Jing Hong, Gege Xiao, Honqiang Qu. Clinical outcomes after Descemet’s stripping endothelial keratoplasty using donor corneas from children younger than 3 years. Clin Exp Ophthalmol. 2018t;46(7):721–729.
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Figure 1. Descemet stripping endothelial keratoplasty with suture assisted donor lenticule insertion technique. Scoring of the Descemet membrane using a reverse Terry-Sinskey hook according to the circular mark (Top first); Scraping of the recipient bed with a Terry Scraper (Top second); Pulling the folded donor lenticule into a Busin’s glide with forceps (Top third); Fixing a 10-0 prolene suture as anchoring stitch on the donor lenticule at 6 o’clock position (Top fourth); Anchoring stitch was placed in anterior chamber and pulled through the incision at 6 o’clock direction with a hook (Bottom first); Donor lenticule delivery with the assistant of Busin’s glide and anchoring stitch (Bottom second); Donor lenticule unfolding in anterior chamber (Bottom third); Air injection to maintain 75% air volume in the anterior chamber (Bottom fourth). Figure 2. Three cases of different ages with congenital hereditary endothelial dystrophy before and after Descemet-stripping endothelial keratoplasty (DSEK). Corneal clarity began to improve in the first week after operation and continued to improve during the period of follow-up, presenting that the younger the age, the faster the recovery of corneal transparency (Left three columns). Anterior segment optical coherence tomography (Right column) showed the attached lenticules at 3 months after operation. (Pre-OP: pre-operation, 1w Post-OP: one week post-operation, 1m Post-OP: one month post-operation, 3m Post-OP: three months post-operation)
1
Table 1 Pre-operation and post-operation clinical data of the CHED patients in two groups Age of OP
Group
Patient
(Year/Month)
(Child/Infant
Number
Gender
Eye
BCVA pre-OP
BCVA post-OP
ECL (last
(Log MAR)
(last follow-up,
follow-up, %)
CTS (7th day
Follow-u
Complication
p (Year)
post-OP)
Log MAR)
：M
I
：
M
OD
No FF
0.18
NA
NA
4
No
：M
I
：
M
OS
No FF
0.18
NA
NA
4
No
8M
I
12
M
OD
No FF
0.4
NA
2
2.7
No
9M
I
14
F
OD
No FF
0.4
NA
1
2.：
No
9M
I
14
F
OS
No FF
0.48
NA
2
2.：
No
10 M
I
9
F
OD
No FF
0.3
NA
2
3.2
No
10 M
I
9
F
OS
No FF
0.3
NA
2
3.2
No
11 M
I
1：
M
OD
No FF
FC but UCVC
NA
2
2.5
No
11 M
I
1：
M
OS
No FF
FC but UCVC
NA
2
2.5
No
12 M
I
15
F
OD
No FF
FC but UCVC
NA
1
2.5
No 1
12 M
I
15
F
OS
No FF
2Y
C
1
F
OD
FF
but
FC but UCVC
NA
1
2.5
No
0.88
NA
-1
8.5
Dislocation and
UCVC
converted
to
PK 2Y
C
1
F
OS
FF
but
0.4
45
-1
8.3
UCVC 3Y
C
3
M
OD
HM
Reposition but
0.3
53
-1
：.8
UCVC 3Y
C
3
M
OS
HM
Dislocation and
Dislocation and Reposition
but
0.3
22
1
：.8
No
UCVC 4Y
C
5
F
OD
FC
0.48
30
2
4.1
No
4Y
C
5
F
OS
FC
0.48
21
2
4.1
No
4Y
C
7
M
OD
HM
0.7
NA
1
3.3
No
4Y
C
7
M
OS
HM
0.48
NA
1
3.3
No
2
：Y
C
11
F
OS
1
0.48
25
1
2.7
No
：Y
C
13
F
OD
0.88
0.48
NA
2
2.：
No
：Y
C
13
F
OS
0.78
0.4
NA
2
2.：
No
7Y
C
2
M
OD
0.88
0.4
34
0
7.7
No
7Y
C
2
M
OS
0.78
0.4
25
1
7.5
No
8Y
C
4
M
OD
1
0.48
40
2
5
No
8Y
C
4
M
OS
1
0.78
28
2
5
No
12 Y
C
10
M
OD
1
0.7
32
NA
2.9
No
12 Y
C
10
M
OS
1
0.：
24
NA
2.8
No
13 Y
C
8
M
OD
1.5
1
28
2
3.2
No
13 Y
C
8
M
OS
1.5
0.88
30
2
2.8
No
OP
operation
CHED: congenital hereditary endothelial dysfunction 3
ECL: endothelial cell loss CTS: corneal transparency score (Criterion of CTS as follows: -1, worse than preoperative transparency; 0, the same as preoperative transparency; +1, better than preoperative transparency but not completely transparent 1; and +2, transparent.) BCVA: best corrected visual acuity FF: fix and follow HM: hand motion FC: finger count UCVC: unable to cooperate with visual chart
4
Table 2 Averaged
best correct vision acuity pre-operative and post-operative at the last follow-up in the child group and the
infant group Child Group
Infant Group
p
1.03±0.25
NA
NA
11
NA
0.54±0.20
0.32±0.11
N#
18
7
p
<0.001
NA
Pre-operation
Visual
Acuity (LogMAR) N* Post-operation
Visual
0.01
Acuity (last follow-up, LogMAR)
N*: Eight eyes in the child group and all the eyes in the infant group pre-operation were excluded because of noncooperation in vision test or
5
low vision could not be tested with a visual chart. N#: One eye post-operation in the child group was excluded because of conversion to penetrating keratoplasty, and four eyes post-operation in the infant group were excluded because of noncooperation in vision test.
：
Table 3
Comparison for patients in the child group whose best corrected vision acuity at pre-operation and post-operation
were both available Pre-OP
Post-OP
(last
t
p
12.：04
<0.001
follow-up) Best Corrected Visual
1.03±0.25
0.：±0.21
11
11
Acuity (LogMAR) N#
7
DSEK for children with congenital hereditary endothelial dystrophy Different age groups in pediatric patients Long-term outcome
This paper reports a long-term outcome about Descemet stripping endothelial keratoplasty in pediatric patients with congenital hereditary endothelial dystrophy in different age groups. Improved visual outcomes could be achieved in infant patients after the surgery of Descemet stripping endothelial keratoplasty, without a significant increase in complication rates. Suture-assisted donor lenticule insertion techniques, Descemet membrane stripping and postoperative sedation are advocated technical points for this population.
S0002-9394(19)30402-7
DOI:
https://doi.org/10.1016/j.ajo.2019.08.010
Reference:
AJOPHT 11048
To appear in:
American Journal of Ophthalmology
Received Date: 25 February 2019 Revised Date:
11 June 2019
Accepted Date: 16 August 2019
Please cite this article as: Yang F, Hong J, Xiao G, Feng Y, Peng R, Wang M, Qu H, Descemet Stripping Endothelial Keratoplasty in Pediatric Patients with Congenital Hereditary Endothelial Dystrophy, American Journal of Ophthalmology (2019), doi: https://doi.org/10.1016/j.ajo.2019.08.010. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Elsevier Inc. All rights reserved.
Descemet Stripping Endothelial Keratoplasty in Pediatric Patients with Congenital Hereditary Endothelial Dystrophy Short title: Long-term Outcomes in Different Age Groups Authors: Fan Yang, Jing Hong, Gege Xiao, Yun Feng, Rongmei Peng, Minshu Wang, Hongqiang Qu Affiliation: Department of Ophthalmology, Peking University Third Hospital Beijing Key Laboratory of Restoration of Damaged Ocular Nerve, Peking University Third Hospital
Abstract Purpose: To report the long-term outcomes of Descemet stripping endothelial keratoplasty (DSEK) with suture-assisted donor lenticule insertion performed in different age groups for the pediatric patients with congenital hereditary endothelial dystrophy (CHED). Design: Retrospective case series. Methods: Pediatric patients with CHED who underwent DSEK from January 2010 to January 2016 were enrolled. Patients were divided into two groups according to their ages: the infant group and the child group. Long-term clinical outcomes and complications were compared between the two groups. Results: 30 eyes of 16 patients were included, 19 eyes (10 patients) in the child group and 11 eyes (6 patients) in the infant group. Average follow-up period was 4.08±1.90 years (ranged from 2.5 years to 8.5 years). Corneal transparency scores of the two groups on the seventh day postoperatively did not have statistic difference. Averaged postoperative best corrected visual acuity (BCVA) in the infant group (LogMAR 0.32±0.11) was better than that in the child group (LogMAR 0.54±0.20) p=0.01 . 33% cases in the child group and 86% cases in the infant group had postoperative BCVA achieved or better than LogMAR 0.4. Average endothelial cell loss in the child group was 31.21±9.17%. Lenticule detachment occurred in three cases of the child group. Conclusions: Improved visual outcomes could be achieved in infant CHED patients after DSEK, without significant rise of complication. Suture-assisted donor lenticule insertion techniques, DM stripping and postoperative sedation are advocated technical points.
1
Descemet Stripping Endothelial Keratoplasty in Pediatric Patients with Congenital Hereditary Endothelial Dystrophy Short title: Long-term Outcomes in Different Age Groups
Authors: Fan Yang, Jing Hong, Gege Xiao, Yun Feng, Rongmei Peng, Minshu Wang, Hongqiang Qu Affiliation: Department of Ophthalmology, Peking University Third Hospital Beijing Key Laboratory of Restoration of Damaged Ocular Nerve, Peking University Third Hospital Address: 49# North Garden Road, Hai Dian District, Bei Jing, China
Corresponding Author: Jing Hong Affiliation: Department of Ophthalmology, Peking University Third Hospital Beijing Key Laboratory of Restoration of Damaged Ocular Nerve, Peking University Third Hospital Address: 49# North Garden Road, Hai Dian District, Bei Jing, China Postal Code: 100191 Email: [email protected] Fax: 8610-82089951 Phone: 8610-82266566
1
Introduction Congenital hereditary endothelial dysfunction (CHED), which is characterized by bilateral diffuse corneal edema, typically presents at birth or in early infancy as a common cause of childhood corneal opacification and often results in amblyopia 1,2. Histopathologically, corneal edema is attributable to abnormalities in the Descemet-endothelium complex: diffuse thickening and lamination of Descemet’s membrane (DM) and sparse and atrophic endothelial cells 3,4. Although CHED is primarily a disease of the corneal endothelium and DM, penetrating keratoplasty (PK) has been the traditional mainstay of treatment for these patients 5-7. However, PK is a challenging task in pediatric patients compared with adults. Low scleral rigidity and positive vitreous pressure offer a high risk of vision-threatening complications during surgery, such as suprachoroidal hemorrhage. Compared with adults, pediatric patients after PK always face an increased risk of infection and rejection due to frequent suture loosening, which requires early exchange or removal and subsequent general anesthesia support 7-9. Even when clear grafts are obtained, visual rehabilitation may be complicated by intractable amblyopia due to high and unpredictable astigmatism. In addition, late traumatic dehiscence in PK wounds is more common in children than in adults 10,11, given the unpredictable nature of their daily activities. For these reasons, surgery has often been avoided or delayed for as long as possible in children with CHED, which often compromises the visual development of these patients 11. Currently, targeted corneal endothelium transplantation techniques, such as Descemet stripping endothelial keratoplasty (DSEK), have been preferred over PK for endothelial dysfunctions in children because of the advantages of rapid visual recovery, stabilized refractive error, decreased likelihood of amblyopia, and decreased risk of traumatic globe rupture. Despite these advantages, there are few series describing DSEK in pediatric patients with CHED 12-14 and even fewer involving infants 15-18. This series reported the outcomes of DSEK performed in 30 phakic eyes of 16 pediatric patients with CHED in different age groups.
Materials and Methods This retrospective cohort study was approved by the Institutional Review Board of Peking University Third Hospital. The informed consents of embracing images and data in this study were received from the patients’ parents. The medical records and eye bank records of all the CHED pediatric patients who underwent DSEK performed by Professor Hong Jing at the Ophthalmology Department of Peking University Third Hospital from January 2010 to January 2016 were analyzed. Patients were divided into two groups according to their ages at the time of surgery: the infant group included patients younger than 1 year old, and the child group included patients 1 year old or older. Retrospective data collection included demographics, family histories, and past medical and ocular surgical histories. Other preoperatively recorded data included the best corrected visual acuity (BCVA) (LogMAR visual chart), intraocular pressure (IOP), slit-lamp biomicroscopy findings and endothelial density of the donor tissue. 2
Surgical Technique The main surgical steps are illustrated in Figure 1. Preparation of the Donor Tissue The donor tissues stored in McCarey Kaufman (MK) medium were obtained from the Eye Bank of Peking University Third Hospital and were evaluated for suitability for DSEK. The donor graft dissection was performed with a Moria CB microkeratome (head 350-400 µm blade depth) (Moria Surgical, Doylestown, PA) in 26 eyes and manually using a Moria ALTK artificial anterior chamber (Moria Surgical, Doylestown, PA) in 4 eyes due to the flexible characteristics of the tissues of pediatric donors younger than two years of age. The donor tissues were prepared by the surgeon immediately before surgery, and the dissected buttons were stored in MK medium during the surgical interim. Preparation of the Recipient Bed All surgeries were performed under general anesthesia. A circular mark with a diameter of 7.5 or 8.0 mm was made on the anterior corneal surface to delineate where to strip DM. A main scleral tunnel was made at the 12 o’clock position. Using Healon GV (Abbott Medical Optics, Abbott Park, Illinois, USA) to maintain the anterior chamber, scoring of DM with a reverse Terry-Sinskey hook (Bausch and Lomb Surgical, St. Louis, MO, USA) and scraping of the recipient bed with a Terry Scraper (Bausch and Lomb Surgical) were performed. All of the removed DM specimens were sent for pathological analysis. Donor Lenticule Insertion Because of the phakic status of all these patients, pilocarpine was applied preoperatively to protect the transparent crystalline lenses, and the donor lenticule was inserted into the anterior chamber using a suture-assisted donor lenticule insertion technique 19-21 to minimize manipulations in the anterior chamber. The donor lenticule overlying a bed of cohesive viscoelastic was carefully folded and pulled into Busin’s glide (Moria Inc. Doylestown, PA, US) with forceps, and a 10-0 prolene suture was fixed at the 6 o’clock position as anchoring stitch. The anchoring stitch was tied to create a loop, after which it was placed in the anterior chamber and pulled through the incision in the 6 o’clock direction with a hook. After evacuation of all the viscoelastic material, an anterior chamber maintainer was inserted through the temporal incision to provide irrigation. The donor lenticule was pulled into the anterior chamber through the main scleral tunnel at the 12 o’clock position with the assistant of Busin’s glide and the anchoring stitch. Once inserted, the donor lenticule was unfolded in balanced salt solution (BSS, Alcon, Fort Worth, TX, USA). To prevent postoperative pupillary block by air bubbles, peripheral iridectomy was performed. Then, the scleral incision was interrupted sutured with 10-0 prolene sutures. The anchoring stitch was cut after the donor lenticule was positioned and centered. A complete air fill was performed and maintained for 10 minutes, followed by gentle partial release of air to maintain 75% air volume in the anterior chamber. The patient was maintained in the supine position for four hours. For children who could not cooperate, postoperative sedation was provided by an anesthesiologist. Postoperative Management 3
Postoperatively, topical drops including 1% prednisolone acetate, tobramycin (Tobrex, Alcon Laboratories, Inc., Fort Worth, TX), cyclosporin (1%, North China Pharmaceutical Company, Ltd., Shijiazhuang, Hebei Province, China) and artificial tears four times daily were prescribed for the first week. The dosages were reduced gradually as clinically indicated and stopped 12 months after surgery. Patients were reviewed at 1, 3, 7, and 30 days and 3, 6, and 12 months postoperatively and once per year thereafter. BCVA was tested at each visit using a LogMAR visual chart. For patients who were too young to cooperate for the vison test, whether they could fix and follow (FF) light was checked using a torch. IOP (noncontact tonometer), lenticule status, corneal clarity, and complications were recorded at each visit. Anterior segment optical coherence tomography (AS-OCT, Carl Zeiss Meditec, Dublin, CA) and endothelial evaluation with confocal microscopy (HRT-RCM, Heidelberg Engineering, GmBH, Dossenheim, Germany) were performed when possible and appropriate. Sutures were removed within the first month postoperatively. All of these patients were referred to a pediatric ophthalmologist for amblyopia therapy one month after DSEK. Statistics Postoperative corneal transparency was scored according to slit-lamp photos taken on the 7th day postoperatively compared with preoperative photos. The criterion of corneal transparency scores (CTS) were as follows: -1, worse than preoperative transparency; 0, the same as preoperative transparency; +1, better than preoperative transparency but not completely transparent 1; and +2, transparent. Differences in postoperative corneal transparency between the two groups were compared with the Mann-Whitney rank-sum test. The differences in BCVA between the two groups were compared with independent samples t-tests. Patients in the child group whose pre-operation and post-operation BCVA were both available were compared with paired samples t-test. Histopathology of Removed DM Specimens To assess the pathologic features of DM and the endothelium in CHED, histopathologic procedures were performed in all the removed DM specimens, including hematoxylin-eosin and periodic acid-Schiff staining. Then, the samples were observed by light microscopy (Cytation5, BioTek, Winooski, VT, USA, original magnification ×100). One of the removed DM specimens was further inspected using scanning electron microscopy. The sample was fixed with 2% glutaraldehyde in an 80 mM sodium cacodylate buffer (pH 7.2–7.4, 320–340 mOsm/kg), processed with gold-coated magnetic particles for solid-phase immunoassays and, after the critical point of drying, examined with a scanning electron microscope (JEOL JSM-7000F, JEOL, Peabody, USA). The sample was screened at low magnification (original magnification ×30–×200) and pictured at higher magnifications (original magnification×60.000).
Results Pre-operation and post-operation clinical data of the CHED patients in this study was listed in Table 1. 4
Thirty eyes of 16 pediatric patients were included in this study, including 9 boys and 7 girls aged from 6 months to 13 years old (average, 4.35±4.03 years old). There were 10 patients (19 eyes) in the child group with an average age of 6.50±3.66 years old and 6 patients (11 eyes) in the infant group with an average age of 0.78±0.18 years old. The average follow-up period was 4.08±1.90 years (ranging from 2.5 years to 8.5 years). In the child group, one child had a positive family history of an affected brother, two children had a surgical history of trabeculectomy, one child had a surgical history of PK in the contralateral eye, and two children had disease complicated by nystagmus. The preoperative visual acuity in the child group ranged from FF to LogMAR 1.0, and the average visual acuity was LogMAR 1.03±0.25 (n=11, excluding patients who were unable to cooperate). No family history or surgical history was reported in the infant group, and the preoperative vision test was no FF in all infant eyes. All patients in the two groups had diffuse, bilateral corneal edema, clear crystalline lenses, normal IOP and corneal diameter. The clinical diagnosis of CHED was further confirmed by histopathologic analysis of the removed DM specimens showing marked thickening and lamination of DM and an absence of endothelial cells. The scanning electron microscope images showed no endothelial cells on either side of the removed DM. The surgical procedures were smooth, and crystalline lenses were reserved in all the cases. Lenticule detachment occurred in three eyes in the child group within the first 24 hours after surgery. Two eyes were managed successfully by rebubbling, but it was difficult to reposition the lenticule in the other eye. After several times to reposition, detachment always recurred at the second day after repositioning, at last PK was performed for this eye at request of parents one month after DSEK. All other lenticules remained well attached, as confirmed by anterior segment OCT. No other surgical complications, such as pupillary block, acute cataract formation or primary graft failure, were observed. Corneal transparency began to improve within the first week after surgery and continued to improve for almost one year, presenting that the younger the age, the faster the recovery of corneal transparency (Figure2). However, CTS was12.26 in the child group (n=17) and 15.83 in the infant group (n=9) at the 7th day postoperatively, with no difference in statistic (p=0.21, two eyes in each group were excluded because of failure to take photos at the follow-up day). Vision acuity improved rapidly with corneal transparency after surgery. All patients in the infant group could achieve FF as early as the first week after DSEK, whereas no patient could do that preoperatively. All patients in the child group and four patients in the infant group were already able to cooperate in visual acuity testing with a visual chart before the last review. The average BCVA in the infant group (LogMAR 0.32±0.11) was statistically better than that in the child group (LogMAR 0.54±0.20) (p=0.01) (Table 2). The postoperative BCVA of 6 eyes (33%) in the child group and 6 eyes (86%) in the infant group had achieved LogMAR 0.4 or better at the last follow-up (Table 1). The average BCVA in the child group improved from LogMAR 1.03 preoperatively to LogMAR 0.54 postoperatively (Table 2).Patients in the child group whose pre-operation and post-operation BCVA were both available were compared, with the result LogMAR 1.03±0.25 preoperative improved to LogMAR 0.6±0.21postoperative (Table 3). Two patients in the child group in this series underwent DSEK in one eye and PK in the contralateral 5
eye. Both patients obtained better BCVA in DSEK eyes, although corneal transparency in the DSEK eye never reached the quality of the PK eye due to residual stromal haze. Endothelial cell density was evaluated with confocal microscopy in 8 patients (14 eyes, excluding the patients who could not cooperate or converted to PK) in the child group (Table 1). The average endothelial cell loss (ECL) in the child group was 31.21±9.17% at the most recent review. All patients in the infant group were still too young to cooperate for this examination. There were no signs of endothelial rejection or graft dysfunction in any of the eyes in the two groups until the final visit.
Discussion DSEK offers several advantages over PK for pediatric patients with CHED. This technique is performed under “closed system” conditions; therefore, the risk of surgical complications accompanied by low IOP can be minimized. The small corneal incision required for DSEK is unlikely to dehisce due to trauma. Few sutures and early suture removal may help to reduce the endothelial rejection rate and suture-related infections. Rapid recovery and mild astigmatism facilitate visual rehabilitation and treatment of amblyopia. However, until recently, no definitive evidence of the appropriate timing for DSEK in pediatric patients with CHED has been determined, as the profit of early visual rehabilitation must be weighed against the increased risk of surgical complications in children. Although some series with a small sample size 12-18 and isolated case reports 22-26 have reported DSEK in CHED children, no study has ever compared DSEK outcomes between different age groups among pediatric CHED patients. To the best of our knowledge, until now, this series had the largest sample size and the longest observation period for evaluating DSEK performed in CHED children and for comparing infant patients and older pediatric CHED patients. The visual outcomes of this case series were encouraging. Vision acuity improved rapidly with corneal transparency after surgery. The average BCVA was LogMAR 0.32 in the infant group and LogMAR 0.54 in the child group. The postoperative BCVA in 33% of eyes in the child group and 86% of eyes in the infant group had achieved than LogMAR 0.4 or better. Patients in the infant group had statistically better results in terms of postoperative BCVA than those in the child group, which may be due to relieving form deprivation and beginning amblyopia treatment at a younger age. In previous reports, the visual outcomes of CHED children were varied. In a report by Busin and colleagues 15, who recruited pediatric patients and adult patients, 8 of 9 eyes achieved a BCVA of 20/40 or better. In the report by Silvana and colleagues 18, which included pediatric patients with various indications, the BCVA was better than 20/40 in 8 of the 13 eyes. Sporadic case reports also presented varying BCVAs: 20/100 for a 19-year-old patient 27 and 20/50 for an 8-year-old girl 25. Regarding infant patients, Lenhart and colleagues 16 reported that an 8-month-old CHED patient had an uncorrected visual acuity of 20/40 at 24 months' follow-up after DSAEK. The wide variations in these reports might be due to different baseline conditions and different surgeons. Besides, the patient’s age was another undeniable important influencing factor. This study confirmed that good visual outcomes could be achieved after DSEK in infant CHED patients with the assistance of timely amblyopia treatment, while it was not so 6
satisfactory in older children. Worse postoperative visual acuity in the child group compared with the infant group in this series could reflect from one aspect the influence of amblyopia on older children with CHED. Although the optimal age for DSEK remains controversial, early surgical intervention should be advocated in the view of avoiding amblyopia. In this series, two patients in the child group underwent DSEK in one eye and PK in the contralateral eye. Although corneal transparency in the DSEK eye never reached the quality of PK eye due to residual stromal haze, both patients obtained better BCVA in the DSEK-treated eyes compared with the PK-treated eyes, and they both preferred the visual quality of the former. Early visual stabilization and the predictable nature of refraction error might offer more advantages in terms of amblyopia management in DSEK-treated eyes. The anatomical outcome of improvement in corneal transparency in this series was similar to that in previous reports about DSEK in CHED 12,18,27. Corneal clarity began to improve within the first week after surgery and continued to improve for almost one year. Patients in the infant group seemed to have faster recovery of corneal transparency than those in the child group, although the rough comparison of corneal transparency recovery and the small number of cases in this series prevented determining a quantitative difference in terms of statistics (p=0.21, Figure 2,). The recovery rate of corneal transparency might be related to the duration of corneal stromal edema, which is requires further observation and more cases to confirm. While early surgical intervention is advocated in children to avoid amblyopia, technical problems are challenges to be overcome to improve the safety of DSEK. The presence of a clear crystalline lens with normal accommodative function and a relatively smaller anterior chamber provides challenges to performing the operation of DSEK in the pediatric age group. Crystalline lenses were successfully reserved in all the cases in the two groups in this series. It is extremely important to protect the transparent lens in the limited manipulation space during surgery; therefore, DSEK with a suture-assisted donor lenticule insertion technique was advocated, which minimized the necessity for surgical instruments to enter the anterior chamber 20-22. The donor lenticule was pulled into the anterior chamber with an anchoring stitch, with no instrument reaching the pupil area during delivery, which reduced the risk of accidental lens damage. The suture-assisted donor lenticule insertion technique could also help to shorten the main incision because Busin’s glide did not enter the anterior chamber. The incision with a diameter of 3.5 mm used in this series was smaller than that used in previous reports 13,14 about DSEK for CHED in children, and this smaller incision may benefit patients with milder astigmatism and be less likely to dehisce due to trauma. The inability to identify or strip DM in infants < 12 months of age is another technical challenge that has been previously proposed 12,14,15,17,26, because DM in infants appears much thinner than in adults or older children. Due to poor visualization as a consequence of severe corneal edema, endothelial keratoplasty without DM stripping has been advocated for infants in some studies 12,14,15,17,26 . Busin and colleagues 15 described their experience of performing non-DM stripping endothelial keratoplasty in CHED. The authors left DM intact without removal in infants in whom DM was not visualized. However, of these six eyes, four developed lenticular dislocation on the 2nd postoperative day. Therefore, the role of this modified procedure has still been debated 7
13,27
. In this series, although DM was hardly visible and appeared firmly adherent to the underlying stroma, stripping DM was successful in all infant patients after considerable effort. Subsequent pathology examinations revealed remarkable thickening and lamination of the DM and the absence of endothelial cells. Reservation of an abnormal DM during endothelial keratoplasty is an unpredictable factor for the survival of graft endothelium cells, and the fate of donor lenticule is under a constant threat of dislocation in the future because the retained DM has been found to be a significant cause of graft detachment 28,29. Hence, the authors do not advocate for endothelial keratoplasty without DM stripping in infant patients. Graft detachment occurred in three eyes in the child group due to eye rubbing and inability to maintain in the supine position, while no graft detachment occurred in the infant group. Two eyes were repositioned successfully, however, detachment always recurred at the second day after repositioning for the other eye, and PK had to be performed ultimately. The difference in graft detachment rates between the two groups might be explained by the learning curve because all the three graft detachment cases in the child group occurred during the initial stage of this series, and not a single infant patient had undergone surgery at that time. Due to the problems that arose during the early stages, postoperative sedation was provided to babies and young children, which was very helpful. This method was believed to benefit patients who could not maintain body position during the crucial early postoperative period. The rate of graft detachment in this series was 3/30, which was much lower than that in the report by Ashar et al. 12 (2/5) involving deep lamellar endothelial keratoplasty cases and than that in the report by Busin et al. 15 (4/11) involving phakic children with CHED. This difference may be due to the lack of DM stripping in some of the cases in the abovementioned studies; however, it is certainly difficult to compare trials directly, given the differences in patient ages, disease conditions and surgical complications. Four pediatric donor tissues were used in this series, and graft detachment never occurred. Although it was difficult to manipulate and rolling edge deformity was inevitable due to the elastic nature of grafts, the obvious advantage was that grafts offered adequate and high-quality endothelial cells for young patients. Dissection of pediatric donor tissues should be performed manually because of their soft nature. Predictable graft curling and contracture of these infant donor tissue were observed during the first month after surgery and tended to be stable at the third month after surgery, which was consistent with previous experience30. Endothelial rejection or graft dysfunction never occurred in any eye in this series until the final visit. The averaged ECL in the child group was 31.21%, similar to the outcome of 30.0% from the report by Busin et al. 15 and the outcome of 35% from the report by Madi et al. 18. However, ECL was only evaluated in the child group, while all patients in the infant group were still too young to cooperate; thus, it was impossible to compare the two groups, and a longer observation period is necessary to evaluate this aspect. Based on our experience, DSEK could be a good alternative to conventional PK in pediatric patients with CHED. Good visual outcomes can be achieved in infant CHED patients after DSEK, without a significant increase in complication rates, which provides a good opportunity for subsequent visual reconstruction and amblyopia training. Suture-assisted donor lenticule 8
insertion techniques, DM stripping and postoperative sedation are advocated technical points for this population. However, further studies are required; in particular, long-term results from a larger population of DSEK patients are needed.
Acknowledgements This study is supported by National Natural Science Foundation of China (NO.31271045). No financial relationship needs to disclose in this study. Acknowledgement belongs to Miss Pei Zhang and Miss Lixue Shuai for assistance with images collection.
References 1. Thore Schmedt, Mariana Mazzini Silva, Alireza Ziaei, Ula Jurkunas. Molecular Bases of Corneal Endothelial Dystrophies. Exp Eye Res. 2012; 95(1): 24–34. 2. Weiss JS, Møller HU, Lisch W, et al. The IC3D classification of the corneal dystrophies. Cornea 2008;27(suppl 2):S1-S83. 3. Kenyon KR, Antine B. The pathogenesis of congenital hereditary endothelial dystrophy of the cornea. Am J Ophthalmol. 1971;72(4):787–795. 4. Kirkness CM, Mc CartneyA, Rice NS, Garner A, Steele A D. Congenital hereditary corneal edema of Maumenee: its clinical features, management, and pathology. Br J Ophthalmol.1987;71(2):130–144. 5. Graham MA, Azar NF, Dana MR. Visual rehabilitation in children with congenital hereditary endothelial dystrophy. Int Ophthalmol Clin. 2001;41(4):9–18. 6. Javadi MA, Baradaran-Rafii AR, Zamani M et al, Penetrating keratoplasty in young children with congenital hereditary endothelial dystrophy. Cornea. 2003;22(5):420–423. 7. Al-Ghamdi A, Al-Rajhi A, Wagoner MD. Primary pediatric keratoplasty: indications, graft survival, and visual outcome. J AAPOS. 2007;11(1):41–47. 8. Wagoner MD, Al-Ghamdi AH, Al-Rajhi AA. Bacterial keratitis after primary pediatric penetrating keratoplasty. Am J Ophthalmol. 2007;143(6):1045–1047. 9. Huang PT. Penetrating keratoplasty in infants and children. J AAPOS. 2007;11(1):5–6. 10. Williams MA, Gawley SD, Jackson AJ, Frazer DG. Traumatic graft dehiscence after penetrating keratoplasty. Ophthalmology. 2008;115(2):276–278. 11. Vanathi M, Panda A, Vengayil S, Chaudhuri Z, Dada T. Pediatric keratoplasty. Surv Ophthalmol. 2009;54(2):245–271. 12. Ashar JN, Ramappa M, Vaddavalli PK. Paired-eye comparison of Descemet’s stripping endothelial keratoplasty and penetrating keratoplasty in children with congenital hereditary endothelial dystrophy. Br J Ophthalmol. 2013;97(10):1247–1249. 13. Ashar JN, Latha M, Vaddavalli PK. Descemet's stripping endothelial keratoplasty (DSEK) for children with congenital hereditary endothelial dystrophy: surgical challenges and 1-year outcomes. Graefes Arch Clin Exp Ophthalmol. 2012;250(9):1341-1345. 14. Ashar JN, Ramappa M, Chaurasia S. Endothelial keratoplasty without Descemet's stripping in congenital hereditary endothelial dystrophy. J AAPOS. 2013;17(1):22-24. 15. Busin M, Beltz J, Scorcia V. Descemet-stripping automated endothelial keratoplasty for congenital hereditary endothelial dystrophy. Arch Ophthalmol. 2011;129(9):1140-1146. 9
16. Lenhart PD, Evans CT, Beck AD, Lee WB. Visual outcome after Descemet’s stripping automated endothelial keratoplasty in an 8-month old with congenital hereditary endothelial dystrophy. J AAPOS.2013;17(6):637-639. 17. Bellucci R, Chierego C, Bellucci C. Endothelial keratoplasty in a newborn baby with CHED. Cornea. 2011;30(12):1488-1490. 18. Madi S, Santorum P, Busin M. Descemet stripping automated endothelial keratoplasty in pediatric age group. Saudi Journal of Ophthalmology. 2012;26(3):309–313. 19. Macsai MS, Kara-Jose AC. Suture technique for Descemet stripping and endothelial keratoplasty. Cornea. 2007;26(9):1123–1126. 20. Kaiserman I, Bahar I, McAllum P, Slomovic AR, Rootman DS. Suture assisted vs forceps-assisted insertion of the donor lenticula during Descemet stripping automated endothelial keratoplasty. Am J Ophthalmol. 2008;145(6):986–990. 21. Sarnicola V, Toro P. Descemet-stripping automated endothelial keratoplasty by using suture for donor insertion. Cornea. 2008;27(7):825–829. 22. Fernandez MM, Buckley EG, Afshari NA. Descemet stripping automated endothelial keratoplasty in a child. J AAPOS. 2008;12(3):314–316. 23. Jeng BH, Marcotty A, Traboulsi EI. Descemet stripping automated endothelial keratoplasty in a 2-year-old child. J AAPOS. 2008;12(3):317–318. 24. Pineda R, Jain V, Shome D, Hunter DC, Natarajan S. Descemet's stripping endothelial keratoplasty: is it an option for congenital hereditary endothelial dystrophy? Int Ophthalmol. 2010;30(3):307–310. 25. Goshe JM, Li JY, Terry MA. Successful Descemet's stripping automated endothelial keratoplasty for congenital hereditary endothelial dystrophy in a pediatric patient. Int Ophthalmol. 2012;32(1):61-66. 26. Anwar HM, El Danasoury A, Hashem A. Descemet’s stripping automated endothelial keratoplasty for congenital hereditary endothelial dystrophy. Clin Ophthalmol. 2012;6:159-163. 27. Mittal V1, Mittal R, Sangwan VS. Successful Descemet stripping endothelial keratoplasty in congenital hereditary endothelial dystrophy. Cornea. 2011;30(3):354-356. 28. Suh LH, Dawson DG, Mutapcic L, et al. Histopathologic examination of failed grafts in Descemet’s stripping with automated endothelial keratoplasty. Ophthalmology. 2009;116(4):603–608. 29. Shulman J, Kropinak M, Ritterband DC, et al. Failed Descemet-stripping automated endothelial keratoplasty grafts: a clinicopathologic analysis. Am J Ophthalmol. 2009;148(5):752–759. 30. Rongmei Peng, Yuxin Guo, Yuan Qiu, Jing Hong, Gege Xiao, Honqiang Qu. Clinical outcomes after Descemet’s stripping endothelial keratoplasty using donor corneas from children younger than 3 years. Clin Exp Ophthalmol. 2018t;46(7):721–729.
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Figure 1. Descemet stripping endothelial keratoplasty with suture assisted donor lenticule insertion technique. Scoring of the Descemet membrane using a reverse Terry-Sinskey hook according to the circular mark (Top first); Scraping of the recipient bed with a Terry Scraper (Top second); Pulling the folded donor lenticule into a Busin’s glide with forceps (Top third); Fixing a 10-0 prolene suture as anchoring stitch on the donor lenticule at 6 o’clock position (Top fourth); Anchoring stitch was placed in anterior chamber and pulled through the incision at 6 o’clock direction with a hook (Bottom first); Donor lenticule delivery with the assistant of Busin’s glide and anchoring stitch (Bottom second); Donor lenticule unfolding in anterior chamber (Bottom third); Air injection to maintain 75% air volume in the anterior chamber (Bottom fourth). Figure 2. Three cases of different ages with congenital hereditary endothelial dystrophy before and after Descemet-stripping endothelial keratoplasty (DSEK). Corneal clarity began to improve in the first week after operation and continued to improve during the period of follow-up, presenting that the younger the age, the faster the recovery of corneal transparency (Left three columns). Anterior segment optical coherence tomography (Right column) showed the attached lenticules at 3 months after operation. (Pre-OP: pre-operation, 1w Post-OP: one week post-operation, 1m Post-OP: one month post-operation, 3m Post-OP: three months post-operation)
1
Table 1 Pre-operation and post-operation clinical data of the CHED patients in two groups Age of OP
Group
Patient
(Year/Month)
(Child/Infant
Number
Gender
Eye
BCVA pre-OP
BCVA post-OP
ECL (last
(Log MAR)
(last follow-up,
follow-up, %)
CTS (7th day
Follow-u
Complication
p (Year)
post-OP)
Log MAR)
：M
I
：
M
OD
No FF
0.18
NA
NA
4
No
：M
I
：
M
OS
No FF
0.18
NA
NA
4
No
8M
I
12
M
OD
No FF
0.4
NA
2
2.7
No
9M
I
14
F
OD
No FF
0.4
NA
1
2.：
No
9M
I
14
F
OS
No FF
0.48
NA
2
2.：
No
10 M
I
9
F
OD
No FF
0.3
NA
2
3.2
No
10 M
I
9
F
OS
No FF
0.3
NA
2
3.2
No
11 M
I
1：
M
OD
No FF
FC but UCVC
NA
2
2.5
No
11 M
I
1：
M
OS
No FF
FC but UCVC
NA
2
2.5
No
12 M
I
15
F
OD
No FF
FC but UCVC
NA
1
2.5
No 1
12 M
I
15
F
OS
No FF
2Y
C
1
F
OD
FF
but
FC but UCVC
NA
1
2.5
No
0.88
NA
-1
8.5
Dislocation and
UCVC
converted
to
PK 2Y
C
1
F
OS
FF
but
0.4
45
-1
8.3
UCVC 3Y
C
3
M
OD
HM
Reposition but
0.3
53
-1
：.8
UCVC 3Y
C
3
M
OS
HM
Dislocation and
Dislocation and Reposition
but
0.3
22
1
：.8
No
UCVC 4Y
C
5
F
OD
FC
0.48
30
2
4.1
No
4Y
C
5
F
OS
FC
0.48
21
2
4.1
No
4Y
C
7
M
OD
HM
0.7
NA
1
3.3
No
4Y
C
7
M
OS
HM
0.48
NA
1
3.3
No
2
：Y
C
11
F
OS
1
0.48
25
1
2.7
No
：Y
C
13
F
OD
0.88
0.48
NA
2
2.：
No
：Y
C
13
F
OS
0.78
0.4
NA
2
2.：
No
7Y
C
2
M
OD
0.88
0.4
34
0
7.7
No
7Y
C
2
M
OS
0.78
0.4
25
1
7.5
No
8Y
C
4
M
OD
1
0.48
40
2
5
No
8Y
C
4
M
OS
1
0.78
28
2
5
No
12 Y
C
10
M
OD
1
0.7
32
NA
2.9
No
12 Y
C
10
M
OS
1
0.：
24
NA
2.8
No
13 Y
C
8
M
OD
1.5
1
28
2
3.2
No
13 Y
C
8
M
OS
1.5
0.88
30
2
2.8
No
OP
operation
CHED: congenital hereditary endothelial dysfunction 3
ECL: endothelial cell loss CTS: corneal transparency score (Criterion of CTS as follows: -1, worse than preoperative transparency; 0, the same as preoperative transparency; +1, better than preoperative transparency but not completely transparent 1; and +2, transparent.) BCVA: best corrected visual acuity FF: fix and follow HM: hand motion FC: finger count UCVC: unable to cooperate with visual chart
4
Table 2 Averaged
best correct vision acuity pre-operative and post-operative at the last follow-up in the child group and the
infant group Child Group
Infant Group
p
1.03±0.25
NA
NA
11
NA
0.54±0.20
0.32±0.11
N#
18
7
p
<0.001
NA
Pre-operation
Visual
Acuity (LogMAR) N* Post-operation
Visual
0.01
Acuity (last follow-up, LogMAR)
N*: Eight eyes in the child group and all the eyes in the infant group pre-operation were excluded because of noncooperation in vision test or
5
low vision could not be tested with a visual chart. N#: One eye post-operation in the child group was excluded because of conversion to penetrating keratoplasty, and four eyes post-operation in the infant group were excluded because of noncooperation in vision test.
：
Table 3
Comparison for patients in the child group whose best corrected vision acuity at pre-operation and post-operation
were both available Pre-OP
Post-OP
(last
t
p
12.：04
<0.001
follow-up) Best Corrected Visual
1.03±0.25
0.：±0.21
11
11
Acuity (LogMAR) N#
7
DSEK for children with congenital hereditary endothelial dystrophy Different age groups in pediatric patients Long-term outcome
This paper reports a long-term outcome about Descemet stripping endothelial keratoplasty in pediatric patients with congenital hereditary endothelial dystrophy in different age groups. Improved visual outcomes could be achieved in infant patients after the surgery of Descemet stripping endothelial keratoplasty, without a significant increase in complication rates. Suture-assisted donor lenticule insertion techniques, Descemet membrane stripping and postoperative sedation are advocated technical points for this population.