Abstract
Purpose:
To describe the frequency of postoperative complications in children undergoing penetrating keratoplasty.
Methods:
This retrospective cohort study included pediatric patients (aged 0 to 18 years) in the Intelligent Research in Sight® (IRIS) Registry who underwent primary penetrating keratoplasty between January 2013 and December 2020. Patients were identified using Current Procedure Terminology codes. Postoperative complications were identified using International Classification of Diseases Revision 9 and 10 codes and categorized as complications affecting the anterior segment (epithelial defect, infectious keratitis, neurotrophic keratitis, and glaucoma) or posterior segment (vitreous hemorrhage, retinal detachment, choroid detachment, choroidal hemorrhage, endophthalmitis, epiretinal membrane, and proliferative vitreoretinopathy).
Results:
Of the 544 pediatric patients undergoing penetrating keratoplasty, 259 (47.6%) experienced postoperative complications. Anterior segment complications (n=222, 40.8%) were more common than posterior segment complications (n=96, 17.6%). The most common anterior complication was infectious keratitis (n=163, 30.0%) with a median onset time of 275 days (IQR 50–560 days) after surgery. Vitreous hemorrhage (n=52, 9.6%) and retinal detachment (n=48, 8.8%) were the most common posterior segment complications.
Conclusion:
Infectious keratitis was the most common postoperative complication in children undergoing penetrating keratoplasty. More complications occurred in the anterior segment (70%) of the eye as compared to the posterior segment (30%). These findings demonstrate the challenges associated with pediatric PK and may help guide postoperative monitoring and management.
Keywords: cornea, pediatric penetrating keratoplasty, vitreoretinal complication, retinal detachment, infectious keratitis
Introduction
Penetrating keratoplasty (PK) is the primary surgical intervention for corneal blindness in children.1 The outcomes of PK are less successful in children compared to adults. Factors contributing to the poor outcomes in children include anatomical differences in the pediatric eye such as thin sclera with increased tissue elasticity, lack of positional tissue memory, shallow anterior chamber, and increased positive vitreous pressure.2 Adherence to postoperative treatment regimens also contributes to the challenges of pediatric PK. Young patients are often unable to communicate problems or changes in health status. Surgical success relies on caregivers administering medication and performing visual rehabilitation to treat amblyopia – a major cause of preventable vision loss in children with corneal opacities.3 These factors all contribute to the relatively poorer outcomes seen in pediatric PK.
Postoperative complications following pediatric PK can affect graft survival and visual outcomes. However, pediatric PK is a relatively uncommon procedure, and the incidence of postoperative complications is not well understood. Although infectious keratitis, retinal detachment, and glaucoma have been reported as complications of pediatric PK in the literature, previous studies have included relatively small cohorts ranging from 16 to 165 children.3–7 In this study, we used the IRIS® Registry (Intelligent Research in Sight, Appendix), an electronic health record (EHR) database that includes over 450 million clinical encounters from ophthalmology practices across the United States, to describe the frequency of complications following PK in children.
Methods
Study population and design
This retrospective cohort study used deidentified EHR data from patients followed at practices in the US participating in the IRIS Registry. The database used in this study was frozen on December 24, 2021 and accessed on November 26, 2022. The study was approved by the Massachusetts General Brigham Institutional Review Board with exemption of informed consent. The research adhered to the Declaration of Helsinki.
Inclusion and exclusion criteria
We identified children who underwent PK between 01/01/2013 and 12/31/2020 and between the ages of 0 and 18 years using Current Procedure Terminology (CPT) codes (CPT, 65730, 65750, 65755). Patients undergoing endothelial keratoplasty or deep anterior lamellar keratoplasty were excluded. Patients without a record of the laterality of corneal transplantation were excluded (Supplemental Figure 1).
Outcomes
Complications of pediatric PK were identified using International Classification of Diseases (ICD) Revision 9 and 10 codes (Supplemental Table 1). The postoperative complications were grouped into anterior segment and posterior segment complications. The primary outcome of the study was the frequency and median time between PK and onset of each complication category. The secondary outcome was frequency and time between PK and onset of each complication. We conducted additional analyses on the frequency of postoperative complications stratified by patient age at the time of transplantation and etiology for transplantation (congenital, traumatic acquired, non-traumatic acquired, and other).
Statistical analysis
We report frequencies and percentages for categorical variables and medians and interquartile ranges (IQR) for continuous variables. Chi square tests were used to compare the frequency of complications in the age and etiology-stratified analyses. Kaplan-Meier (KM) estimates were obtained of the 1-year and 3-year cumulative incidence of anterior segment and posterior segment complications. All analyses were performed at the individual level and for children undergoing bilateral PK, the statistical software was used to select an eye at random for inclusion. All analyses were performed using R version 4.3.2 (R Foundation for Statistical Computing).
Results
Demographics
This study included 544 children who underwent PK (43.0% female; n=234). The race and ethnicity of the cohort was 34.7% (n=189) non-Hispanic White, 26.7% (n=145) Hispanic, 19.5% (n=106) non-Hispanic Black, 3.8% (n=21) other and 15.3% (n=83) unknown race. Of note, the other category included Asian, American Indian or Alaska Native, Native Hawaiian or other Pacific Islander, and all other races. The distribution of health insurance type in the cohort was 59.0% (n=321) private insurance, 27.6% (n=150) public insurance, and 13.4% (n=73) unknown. The median age at the time of primary corneal transplant was 15 (IQR 9.0 – 17.0) years. Median follow-up length was 945 (IQR 437 – 1,628) days after PK. In total, 259 patients (47.6%) experienced complications after surgery, with complications further categorized as involving the anterior (n=222, 40.8%) and posterior (n=96, 17.6%) segments of the eye. Of note, some patients experienced complications in both the anterior and posterior segments.
Anterior segment complications
The KM estimated cumulative incidence of anterior segment complications was 25% (95% CI, 21% to 29%) at 1 year and 36% (95% CI, 31% to 41%) at 3 years following PK. The most common anterior segment complication was infectious keratitis (n=163, 30%) with a median time of onset of 275 (IQR 50 – 560) days. The complication that developed most quickly after surgery was that of corneal epithelial defects, with a median time to onset of 38 (IQR 8 – 140) days. 73 (13.4%) patients developed glaucoma postoperatively, which may be attributable to the surgery itself, corticosteroid use, and/or postoperative inflammation. Of note, neurotrophic keratitis was noted in 10 patients (1.8%), with an onset of 546 (IQR 317 – 1,205) days after surgery (Table 1). Anterior segment complications were less frequent among older children (p = 0.008) and more frequent those with traumatic acquired indications for transplantation (p = 0.047; Table 2).
TABLE 1.
Anterior and Posterior Segment Complications after Pediatric Penetrating Keratoplasty
| Patients (n = 544)1 | Time after PK (days)2 | |
|---|---|---|
| Anterior segment | 222 (40.8) | 220 (42 – 456) |
|
| ||
| Infectious keratitis | 163 (30.0) | 275 (50 – 560) |
| Glaucoma | 73 (13.4) | 286 (100 – 754) |
| Epithelial defects | 12 (2.2) | 38 (8 – 140) |
| Neurotrophic keratitis | 10 (1.8) | 546 (317 – 1,205) |
|
| ||
| Posterior segment | 96 (17.6) | 144 (19 – 649) |
|
| ||
| Vitreous hemorrhage | 52 (9.6) | 100 (18 – 488) |
| Retinal detachment | 48 (8.8) | 144 (22 – 711) |
| Endophthalmitis | 27 (5.0) | 74 (32 – 231) |
| Epiretinal membrane | 15 (2.8) | 450 (170 – 699) |
| Vitreous opacity | 11 (2.0) | 762 (127 – 1,334) |
| Choroid detachment | 7 (1.3) | 1,387 (276 – 2,102) |
| Cystoid macular edema | 6 (1.1) | 106 (25 – 118) |
| Choroid hemorrhage | 6 (1.1) | 332 (42 – 908) |
| Proliferative vitreoretinopathy | 2 (0.4) | 928 (665 – 1,192) |
count (percent)
median (interquartile range)
TABLE 2.
Anterior and Posterior Segment Complications Stratified by Age and Indications for Penetrating Keratoplasty
| Anterior segment complications | Posterior segment complications | |||||
|---|---|---|---|---|---|---|
| Yes N = 222 |
No N = 322 |
P-value1 | Yes N = 96 |
No N = 448 |
P-value1 | |
| Age (years) | 0.008 | <0.001 | ||||
|
| ||||||
| ≤4 (N = 90) | 38 (42) | 52 (58) | 27 (30) | 63 (70) | ||
| 5 to ≤10 (N = 70) | 40 (57) | 30 (43) | 18 (26) | 52 (74) | ||
| 11 to ≤18 (N = 384) | 144 (38) | 240 (62) | 51 (13) | 333 (87) | ||
| Indications for Penetrating keratoplasty | 0.047 | <0.001 | ||||
|
| ||||||
| Non-traumatic acquired (N =318) | 132 (42) | 186 (58) | 29 (9) | 289 (91) | ||
| Traumatic acquired (N = 47) | 25 (53) | 22 (47) | 20 (43) | 27 (57) | ||
| Congenital (N = 100) | 46 (46) | 54 (54) | 30 (30) | 70 (70) | ||
| Other (N = 52) | 14 (27) | 38 (73) | 15 (29) | 37 (71) | ||
| Unknown (N = 27) | 5 | 22 | 2 | 25 | ||
Pearson’s Chi-squared test
Posterior segment complications
The KM estimated cumulative incidence of posterior segment complications was 7% (95% CI, 5% to 10%) at 1 year and 10% (95% CI, 7% to 13%) at 3 years following PK. The most common posterior segment complication was vitreous hemorrhage (n=52, 9.6%), which had a median time to onset of 100 (IQR 18 – 488) days. The second most common posterior segment complication was retinal detachment (n=48, 8.8%), with a postoperative time to onset of 144 (IQR 22 – 711) days. Proliferative vitreoretinopathy showed the lowest incidence of 0.4% (n=2) and occurred at a median time of 928 (IQR 665 – 1,192) days. Of note, 27 (5%) of patients developed endophthalmitis at a median time of 74 (IQR 32 – 231) days postoperatively (Table 1). Posterior segment complications were more frequent among younger children (p = 0.002) and those with congenital and traumatic acquired etiologies for transplantation (p < 0.001; Table 2)
Discussion
This IRIS registry-based study provides novel insight into the frequency and timing of complications following pediatric PK. Although corneal transplantation is the most commonly performed form of solid-organ transplantation in the United States, it is relatively infrequently performed in children.8 PK is generally a successful procedure in adults in the ‘low-risk’ (avascular and uninflamed) setting, where the rate of graft failure can be as low as 19.7% at 5 years.9 In contrast, PK in children tends to be less successful, with graft failure rates ranging from 31 to 67% at 6 months to 26 months postoperatively.3–5,7 This study analyzed the common complications found in both anterior and posterior segments after PK in children, reinforcing the need for these patients to be monitored closely for conditions that can threaten graft survival and visual outcomes. We hope this study provides insights on complications that may require early intervention before graft failure.
The most common anterior segment complication in our study was infectious keratitis, which was noted in 30% of patients. This is comparable to reported incidences of infectious keratitis following pediatric PK in the literature, which range from 10 to 50%.3,4,10,11 This is in contrast to adults, where the incidence has been reported to range between 0.02% and 7.9%.12 It is possible that differences in the specificity of identifying infectious keratitis through retrospective chart review, compared to using diagnostic billing codes, may contribute to differences between reported incidences in the literature and the current study, but it is also important to recognize that infectious keratitis after PK in children may arise from challenges specific to children, particularly with respect to treatment adherence and ability to communicate postoperative concerns. This is in addition to other factors that predispose to infectious keratitis that affect both children and adults, including delayed re-epithelialization, neurotrophic keratitis, loose/exposed sutures, suture removal and ocular surface disorders (i.e., dry eye).7,11 Infectious keratitis following PK can be further analyzed by considering issues related to donor versus host tissue. Infectious keratitis and endophthalmitis due to contamination of donor tissue was a concern in the past. However, standard treatment with donor tissue using povidone-iodine has been commonly used for its lower cellular toxicity and higher antimicrobial activity in comparison to alternative antibiotics.13 Host-related issues, such as pre-existing ocular surface disorders, have been reported to lead to a 2.3-fold increase in the risk of developing graft infection as compared to patients without ocular surface disorders.14 Additionally, topical steroid use may also contribute to infections following keratoplasty.14
In terms of posterior segment complications, vitreous hemorrhage was the most common complication in our study following pediatric PK, affecting 9.6 % (n=52) of patients. This was followed by retinal detachment and endophthalmitis. We noted retinal detachment in 8.8% (n=48) of patients, which is similar to reports in the literature which range from 3 to 9.7%.6,15 Postoperative endophthalmitis is a rare but devastating complication after PK resulting from infection in the posterior segment of the eye. In our study endophthalmitis was observed in 5% (n=27) of patients. This is relatively higher than reported incidences in adults, which range from 0.11 to 1.05%16–18. In children, the rate of endophthalmitis after PK has been reported to range from 1.5 to 4.2%,5,6 in line with our findings.
The pediatric eye is anatomically different from that of the adult in multiple ways, including overall size, a shallower anterior chamber, increased tissue elasticity, and increased risk of positive vitreous pressure (PVP). These anatomical factors may contribute to several of the complications reported here. The shallow anterior chamber and narrow irido-corneal angle predisposes pediatric patients to development of anterior synechiae and intraocular pressure (IOP) elevation, the rates of which are higher in children as compared to adults after PK2. We have also included additional data as supplemental figures on the incidence of repeat PK in children within five years following initial transplant (18%) as well as the incidence of repeat PK by age and etiology (Supplemental Figures 1–3).
Our study found that 13.4% of pediatric PK recipients developed glaucoma after surgery, which is on the low end of the reported incidence range of 14 to 33.3%.7,9,10,13,17 In addition, with a reported incidence of 40 – 50%, positive vitreous pressure (PVP) is common in the setting of PK,19 and is due to, at least in part, the anatomy of the pediatric eye. PVP may be a contributing factor to multiple posterior segment complications in pediatric PK, including, as reported here, vitreous hemorrhage (9.6%), retinal detachment (8.8%), choroidal detachment (1.3%), and choroidal hemorrhage (1.1%). Not surprisingly, the rates of all four of these complications in the present study are higher than that reported in adult PK, which have been reported to be 0.75%, 0.5 to 4.7%, 0.7%,20,21 and 0.2 to 0.73%,21,22 respectively.
The unique anatomy of the pediatric eye and the increased risk it imparts for postoperative complications is well known. Interestingly, glaucoma, vitreous hemorrhage, retinal detachment, choroidal detachment, and choroidal hemorrhage all occurred at least several months after surgery in this study, and so whether they are directly attributable to PK is unclear. Indeed, the only complications noted to occur within 3 months of surgery were corneal epithelial defects (median onset of 38 days, IQR 8 – 140 days) and endophthalmitis (median onset of 74 days, IQR 32 – 231 days), both of which may be more directly attributable to surgery.
It is important to acknowledge limitations to our study, which include the retrospective nature of our analysis and limitations inherent to the IRIS Registry. While the IRIS registry is the largest nationwide electronic health record database available to date and includes contributions from thousands of practicing ophthalmologists, this comes with variations in documentation for billing and coding purposes. Thus, we acknowledge the challenge of using CPT and ICD codes to define patients’ postoperative course and complications. Further investigations into risk factors that may contribute to anterior and posterior segments complications, such as pre-operative glaucoma status, may be warranted. In addition, the contribution of postoperative complications to corneal graft survival warrants further study. Finally, children undergoing PK may undergo additional surgical interventions and it is possible that some of the complications identified in this study are attributable to subsequent procedures.
There are many challenges to pediatric PK, beyond graft rejection and failure. Like their adult counterparts, pediatric PK patients are at risk for multiple postoperative complications, which is compounded by limited cooperation, limited compliance, and unique anatomy; in addition, many of these complications can directly or indirectly lead to corneal graft failure. Interestingly, for many of the reported complications, such as infectious keratitis, retinal detachment, choroidal detachment, and choroidal hemorrhage, we found higher rates than that reported in adults. Whether this is related to the retrospective nature of this study and reliance on ICD codes in the IRIS Registry is unknown, but it nonetheless emphasizes the overall high-risk nature of pediatric PK and the need for a team approach with close monitoring for each patient to optimize outcomes.
Supplementary Material
Financial Support:
NIH K08 EY EY031759 (THD) and K12 TR004381 (IO)
Appendix:
Members of the IRIS® Registry Analytic Center Consortium:
Suzann Pershing, MD;1 Leslie Hyman, PhD;2 Julia A. Haller, MD;2 Aaron Y. Lee, MD, MSCI;3,4 Cecilia S. Lee, MD, MS;4 Flora Lum, MD;5 Joan W. Miller, MD;6 Alice C. Lorch, MD, MPH6
1. Stanford University, Palo Alto, CA, USA
2. Wills Eye Hospital, Philadelphia, PA, USA
3. eScience Institute, University of Washington, Seattle, WA, USA
4. Department of Ophthalmology, University of Washington, Seattle, WA, USA
5. American Academy of Ophthalmology, San Francisco, CA, USA
6. Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA
Footnotes
Conflict of Interest: No conflicting relationship exists for any author.
References:
- 1.Zhu AY, Marquezan MC, Kraus CL, Prescott CR. Pediatric Corneal Transplants: Review of Current Practice Patterns. Cornea. 2018;37(8):973–980. doi: 10.1097/ICO.0000000000001613 [DOI] [PubMed] [Google Scholar]
- 2.Hwang DG, Hwang PH. Pediatric Penetrating Keratoplasty. Semin Ophthalmol. 1991;6(4):212–218. doi: 10.3109/08820539109060201 [DOI] [PubMed] [Google Scholar]
- 3.Limaiem R, Chebil A, Baba A, Ben Youssef N, Mghaieth F, El Matri L. Pediatric Penetrating Keratoplasty: Indications and Outcomes. Transplant Proc. 2011;43(2):649–651. doi: 10.1016/j.transproceed.2011.01.055 [DOI] [PubMed] [Google Scholar]
- 4.Dana MR, Moyes AL, Gomes JAP, et al. The Indications for and Outcome in Pediatric Keratoplasty. Ophthalmology. 1995;102(8):1129–1138. doi: 10.1016/S0161-6420(95)30900-1 [DOI] [PubMed] [Google Scholar]
- 5.Cowden JW. Penetrating Keratoplasty in Infants and Children. Ophthalmology. 1990;97(3):324–329. doi: 10.1016/S0161-6420(90)32586-1 [DOI] [PubMed] [Google Scholar]
- 6.Al-Ghamdi A, Al-Rajhi A, Wagoner MD. Primary pediatric keratoplasty: Indications, graft survival, and visual outcome. Journal of American Association for Pediatric Ophthalmology and Strabismus. 2007;11(1):41–47. doi: 10.1016/j.jaapos.2006.09.012 [DOI] [PubMed] [Google Scholar]
- 7.Xavier dos Santos Araújo ME, Santos NC, Souza LB de, Sato EH, de Freitas D. Primary Pediatric Keratoplasty: Etiology, Graft Survival, and Visual Outcome. Am J Ophthalmol. 2020;212:162–168. doi: 10.1016/j.ajo.2019.12.013 [DOI] [PubMed] [Google Scholar]
- 8.Black CK, Termanini KM, Aguirre O, Hawksworth JS, Sosin M. Solid organ transplantation in the 21st century. Ann Transl Med. 2018;6(20):409-409. doi: 10.21037/atm.2018.09.68 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Wagoner MD, Gonnah ES, Al-Towerki AE. Outcome of primary adult optical penetrating keratoplasty with imported donor corneas. Int Ophthalmol. 2010;30(2):127–136. doi: 10.1007/s10792-009-9295-x [DOI] [PubMed] [Google Scholar]
- 10.Kusumesh R, Vanathi M. Graft rejection in pediatric penetrating keratoplasty: Clinical features and outcomes. Oman J Ophthalmol. 2015;8(1):33. doi: 10.4103/0974-620X.149862 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Wagoner MD, Al-Ghamdi AH, Al-Rajhi AA. Bacterial Keratitis After Primary Pediatric Penetrating Keratoplasty. Am J Ophthalmol. 2007;143(6):1045–1047. doi: 10.1016/j.ajo.2006.12.035 [DOI] [PubMed] [Google Scholar]
- 12.Song A, Deshmukh R, Lin H, et al. Post-keratoplasty Infectious Keratitis: Epidemiology, Risk Factors, Management, and Outcomes. Front Med (Lausanne). 2021;8. doi: 10.3389/fmed.2021.707242 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Gopinathan U, Reddy MK, Nadkarni MS, Dasari S, Rao GN. Antimicrobial Effect of Ciprofloxacin, Povidone—Iodine, and Gentamicin in the Decontamination of Human Donor Globes. Cornea. 1998;17(1):57. doi: 10.1097/00003226-199801000-00008 [DOI] [PubMed] [Google Scholar]
- 14.Vajpayee RB, Sharma N, Sinha R, Agarwal T, Singhvi A. Infectious Keratitis Following Keratoplasty. Surv Ophthalmol. 2007;52(1):1–12. doi: 10.1016/j.survophthal.2006.10.001 [DOI] [PubMed] [Google Scholar]
- 15.Dana MR, Moyes AL, Gomes JAP, et al. The Indications for and Outcome in Pediatric Keratoplasty. Ophthalmology. 1995;102(8):1129–1138. doi: 10.1016/S0161-6420(95)30900-1 [DOI] [PubMed] [Google Scholar]
- 16.Aiello LP. National Outcomes of Penetrating Keratoplasty. Archives of Ophthalmology. 1993;111(4):509. doi: 10.1001/archopht.1993.01090040101041 [DOI] [PubMed] [Google Scholar]
- 17.Lorente MG, González IM, de Lossada CR, et al. Need for a standardized antibiotic prophylaxis in keratoplasty. Eye. 2021;35(12):3440–3441. doi: 10.1038/s41433-020-01311-1 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Borkar DS, Wibbelsman TD, Buch PM, et al. Endophthalmitis Rates and Clinical Outcomes Following Penetrating and Endothelial Keratoplasty. Am J Ophthalmol. 2019;205:82–90. doi: 10.1016/j.ajo.2019.05.004 [DOI] [PubMed] [Google Scholar]
- 19.Chronopoulos A, Thumann G, Schutz J. Positive vitreous pressure: Pathophysiology, complications, prevention, and management. Surv Ophthalmol. 2017;62(2):127–133. doi: 10.1016/j.survophthal.2016.10.002 [DOI] [PubMed] [Google Scholar]
- 20.Aiello LP. National Outcomes of Penetrating Keratoplasty. Archives of Ophthalmology. 1993;111(4):509. doi: 10.1001/archopht.1993.01090040101041 [DOI] [PubMed] [Google Scholar]
- 21.Park Y, Kim MH, Won JY, Kim HS, Park YH. VITREORETINAL COMPLICATIONS AFTER PENETRATING KERATOPLASTY. Retina. 2016;36(11):2110–2115. doi: 10.1097/IAE.0000000000001049 [DOI] [PubMed] [Google Scholar]
- 22.Bandivadekar P, Gupta S, Sharma N. Intraoperative Suprachoroidal Hemorrhage After Penetrating Keratoplasty. Eye & Contact Lens: Science & Clinical Practice. 2016;42(3):206–210. doi: 10.1097/ICL.0000000000000164 [DOI] [PubMed] [Google Scholar]
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