Penetrating keratoplasty in children under 3 years old with congenital corneal opacities

INTRODUCTION

Penetrating keratoplasty (PK) has been the most challenging technique for pediatric and corneal surgeons since its first attempt in 1977 by Waring and Laibson, followed by Stulting in 1984, and Cowden in 1990, where they showed satisfying results. Although the prognosis is not as good as in adults, PK is still considered as the first step preventing irreversible loss of visual function in a child due to amblyopia.Several indications for pediatric PK, including congenital causes of corneal opacities, acquired traumatic and nontraumatic corneal opacities cases.

Early PK is mandatory to achieve optimal visual development and prevent the incidence of amblyopia. The prevalence of congenital corneal opacities is approximately 3/100 000. The leading cause of congenital corneal abnormalities in developed countries is Peter’s anomaly (40.3%), followed by sclerocornea(18.1%), dermoid cyst (15.3%), microphthalmia (4.2%),birth trauma and metabolic diseases (2.8%). Studies reported previously that the range of indication for paediatric PK in cases of congenital diseases lasts from 14% to 64%, while in acquired non-traumatic condition is from 19% to 80%, and acquired traumatic disorders 6% to 29%.

The visual acuity of 7 eyes had improvement post keratoplasty,while six eyes were equal to pre-graft, and three eyes had reduced vision due to the effect of graft failure. In addition,the visual acuity of bilateral CCO, which the PK was done on both, had better outcomes than the unilateral CCO. The visual acuity pre- and post-graft analysis using the Wilcoxon test indicates not significant (=0.34). Nonetheless, 44% had improvement in visual outcomes after PK (Figure 4).A successful PK was performed in a girl with CCO on both of her eyes (Figure 5A). The keratoplasty was done one by one following the availability of the eye donor, in which the left was performed first. We managed the surgery on the right eye eight months later (Figure 5B, 5C). The evaluation six months later showed clear grafts on both eyes with no signs of rejection and graft failure (Figure 6).

公募基金公司的分级基金业务在2015年的股灾后就已经基本停滞。而在这次资管新规中，公募产品和开放式私募产品被明令禁止不得进行份额分级，曾经一度火爆的分级基金被判了死刑。明确了现有的分级基金品种也一样要在过渡期后寿正终寝。看来，监管层对2015年分级基金引发的“闹剧”，比如下折造成投资者巨亏的历史记忆犹新，这类规则比较复杂的金融产品也确实不适合普通的投资者。不过这样一来，市场上现有的分级A中的折价品种，或许存在一些折价收敛带来的投资机会。

Thus, this study aims to evaluate the survival of graft rejection and visual outcomes in five years of follow-up after PK in the presence of various congenital corneal abnormalities in children age less than three years old in Jakarta Eye Center.

SUBJECTS AND METHODS

The importance of pre-operative care is to assess the possible benefits of the surgery outweigh the potential risks and all alternatives of PK have been considered. The evaluation of pre-operative care comprised slit-lamp handled, tonopen, B scan Ultrasonography, fundus retcam, cornea diameter measurement, ERG-VEP, and retinoscopy. For a severe microcornea found during slitlamp examination, then the PK was not advised. In case of cataract, the surgery can be done along with keratoplasty.An ocular pressure above 20 mm Hg found during the IcarePRO tonometer examination should be referred to a glaucoma specialist. The ocular pressure and cornea diameter measurement can be evaluated under anaesthesia, or referred to as evaluation under anaesthesia (EUA). The ERG-VEP was done in EUA to evaluate the function of retina and brain.The results were then consulted to neuro-ophthalmologist to decide whether PK should be done or not. Retina examination is under B scan to evaluate the posterior segment. Retcam was done after keratoplasty to assess in case of opacity in the posterior segment. Afterwards, retinoscopy was done with dilated pupil.

Our study included children under three years old,referred by a pediatric ophthalmologist, which then cornea transplantation was performed by the cornea surgeon, between the year 2014-2019 in Jakarta Eye Center (JEC). The data were collected by a retrospective review of the patient’s medical record with a cohort study design. Children with congenital corneal abnormalities were indicated to undergo surgery.

The ethical approval of this study was given by the Ethic Committee of Jakarta Eye Center and the consents were approved during the informed consent prior to surgery.

All cornea donors were from Santa Lucia Eye Bank, Philippines. The collected donor age was ranged from 17 to 23 years old. The cornea donor size was range of 7-7.5 mm in diameter. The regular cornea size of the recipients was expected to be ranged from 6.5-7 mm. The host-graft disparity was counted as 0.25-0.50 mm.

All surgeries were performed under general anesthesia. The initial step was to remove the recipient’s cornea by partial thickness trephination. A careful excision of the cornea was performed with curved corneal or Vannas scissors. Manual iridectomy was created in the upper iris to prevent the risk of glaucoma later after surgery.A viscoelastic was then required to reform the anterior chamber and protect the iris-lens. The graft was secured using 16 interrupted 10-0 nylon sutures with knots buried.Subconjunctival corticosteroid injection and topical antibiotics were given at the closure of surgery (Figure 1).

Our study suggested pre and post keratoplasty was not significantly improved (that although the visual acuity=0.34), the graft survival rate was found to be promising.The overall mean survival time is 22mo (standard error 2.419),with a survival rate of 83.3% int one year. Although there is a gap between the aged of timing PK, we provide the possibility of improving the visual acuity (44%) with good survival.Moreover, we did achieve our main purpose to stabilize the visual function to prevent blindness. Since the patients in our study were below three years old, even with the following object or light fixation only is satisfying. Ⅰn conjunction with our study, we found this to be similar to the previous studies mentioned above.

The visual acuity and graft survival rate in 6, 12, and 18mo were evaluated by descriptive statistics using percentages. We used Kaplan-Meier to present the graft survival plots showing the association between rejection and age. The survival curve included were age below 24mo and above 24mo when the PK was performed. The visual acuity before and after PK was also analyzed using Wilcoxon signed ranks test.

2.2.5.3 发病条件。在日照充分、土壤干旱、昼夜温差大、多风等条件下易发生。此病发生适温为20～28 ℃，最适相对湿度为52%～75%。海拔较高、昼夜温差大、多风条件有利于此病的发生。

RESULTS

PK was performed in sixteen eyes from eleven patients,comprised of seven girls and four boys within 3 to 36 months old. The median age of the first visit was 12 months old.When the surgery was done, it was 14 until 56 months old,with a median age of 20.5 months old. The follow up was then conducted for patients four months after the surgery until 36mo post PK with the median time of 14.5mo. The total length of follow up was 12 to 55mo. The measured mean IOP was 16.5±3.9 mm Hg (Table 1).All cases had congenital corneal opacification (CCO) with or without microcornea. Of all the patients, four had unilateral CCO, while seven cases were bilateral. PK was performed on both eyes of five cases of bilateral CCO. However, two eyes had severe microcornea, hence the surgery was not advised (Table 1).Thirteen eyes of sixteen operated eyes showed clear grafts with no rejection in the next following months. The three grafts rejection manifested 7 to 13mo after the PK. The graft survival rate of the first 6, 12, and 18mo later of keratoplasty was 100%,83.3%, and 66.7%, respectively, from 14 eyes (Figure 2). The two eyes had times of follow up before six months were excluded consequently. The subsequent two until 21mo, additional cataract surgeries were done in 7 eyes, which had developed a cataract. The other two eyes had band keratopathy after 10-and 24-months post keratoplasty. A scleromalacia occurred in one eye of a patient with cataract 23mo after surgery (Table 1).The graft survival on Kaplan-Meier showed the time of rejection after the grafts were implanted (Figure 3). The groups were divided based on the type of rejection. Eventually, 7 eyes showed no rejection and graft failure at the given time.However, further follow-up not conducted later. Overall,the graft failures occurred in 50% of the operated eyes and post-surgery complications included cataract 43.7%; band keratopathy 12.5%, and scleromalacia 6.25%. However, the overall mean survival time based on the aged timing of surgery before and after 36mo is 22mo (95% confidence interval,standard error 2.419) and no significant difference between the patient’s age underwent PK before and after 36mo of their age(=0.52).

刘志武似乎与他较上劲，冷笑说：“我们查过寄存记录，行李寄存处都是先付费，后取行李，凶手——不，应该说是寄尸者——因为我们还不能确定凶手就一定是寄尸者，先行预付了三天的寄存费，这么热的天，以寄尸者的缜密思维，他难道不知道尸体会发臭吗？这说明，寄尸者或者是凶手早就有预谋的。”

The clinical outcome of PK varies from visual development and restoration, clarity of the graft, risk of rejection and infection, which indicates that corneal transplant is essential.During the period of visual development, visual rehabilitation is required after customized clinical and surgical management to overcome the significant challenges associated with pediatric keratoplasty. In terms of facing the unique challenges of pediatric PK, the importance of pre-operative, intraoperative,and post-operative care should be considered.

DISCUSSION

The development of visual acuity is critical, especially during rapid development in early ages, starting from neonates until the first six months of life. Vision development remains important during preschool years and affects the latter outcomes. Therefore, congenital disorder and trauma disrupt the process of development that would impact the visual system. One of the leading causes of congenital disorders that affect the vision in children is CCO. Thus, the primary aim of pediatric keratoplasty is to improve their visual acuity that was disrupted due to opacity.A study by Zhangreported that the most common indication of PK for children under 12 years old was CCO.The patients were categorized as infants (≥3mo and <4y) or children (≥4y and ≤12y). Ⅰn our study, most patients came within the age of 12 to 36mo. Only five patients came before six months of age. Most parents may not recognize the signs and symptoms as they came later at age 12mo. However,the keratoplasty was done at six months up to a year after the initial visit due to the availability of the eye donor. Most PK was done during infants, while the other three eyes were performed in 42, 46, and 56mo.

A study in Mexico showed the mean graft survival time was 45.6mo (95% confidence interval 31.8-58.4mo, standard deviation 0.069), with a survival rate of 70% at one year.Univariate Cox proportional hazard showed that being<9 years of age at the time of the surgery (=0.023) and corneal dystrophies (=0.04) were prognostic factors for corneal rejection. A 10-year study in Malaysia reported that 18.75% of children who underwent PK were successfully achieved the best-corrected visual acuity of 6/12 or better. A hazy graft was noted in 68.75% of patients and was attributed to graft rejection, glaucoma, and graft failure. Factors contributing to the graft’s survival rate at a one-year postoperative period include the presence of vascularized cornea,intraocular inflammation, and combined surgery, which were significant (<0.05).

为避免城镇用水过度紧张，可以建立企业用户用水优先权制度。对于新增加的城镇企业用水户，必须按照取得用水权的先后顺序、排在老用户之后用水，也就是说老用户拥有优先权，如果水不够用，应先停后来者的用水。这样想要进入城市的企业就要慎重考虑供水风险。这既可以保护老用户的利益、降低已有投资的风险，又可避免缺水城市过度膨胀。

Our study reported three eyes that had a rejection in 7 to 13mo after keratoplasty. Further findings such as band keratopathy,cataract, and scleromalacia were developed later as graft failure. Patients were followed 12 to 56mo after surgery and advised for routine examination and rehabilitation as graft failure can occur later. We suspected that other conditions such as usage of topical steroids, autoimmune or genetic disease disrupted the graft. The PK done by Huangreported that infants frequently have a concomitant eye disease, which requires simultaneous or subsequent procedures, leading to much higher rates of graft rejection. Therefore, managing keratoplasty, especially in children age two years old, is challenging.

A retrospective study by Karadagshowed that the overall mean graft survival time was 45.2±5.8mo, with a survival rate of 75.7% at one year. The 1-year graft survival rate was 51.9% and 90.7% in eyes with and without glaucoma,respectively. Cox proportional hazards regression analysis demonstrated that the presence of glaucoma (=0.014) and concurrent operation during primary keratoplasty (=0.049)were independent prognostic factors for poor graft survival. On the other hand, it was also stated that there was no association between the age of primary keratoplasty (=0.626) and operation before or after primary keratoplasty (=0.800 and=0.104, respectively) that affected with lower graft survival.Half of the patients were able to achieve ambulatory vision at the last follow-up.

A study previously conducted by Di Zazzoconclude that rejection is not a significant predictor of graft failure as most of the graft rejection episodes were successfully treated.A successful restoration comprises a good timely treatment.The use of topical prednisolone 1.0%, or dexamethasone 0.1% drops, once per hour around the clock for one week with a gradual taper, and less potent steroid eye drop of fluorometholone in 3‐6mo is also advisable. Systemic steroid therapy in the form of an intravenous pulse steroid (intravenous dexamethasone 4-5 mg/kg body weight, diluted in 150 mL of 5% dextrose over 30-60 min with monitoring of vital signs may also contribute. Oral systemic steroids (1 mg/kg body weight)can be prescribed after initial pulse therapy in tapering doses,although the efficacy is still unclear. An increased frequency of topical steroids and antibiotics is required for a week after suture removal. Topical cyclosporine (CsA) 2% four times a day, then tapered to twice daily, can reduce the frequency,duration, and subsequent side effects of postoperative topical steroids. Another study combined topical steroids with 2%topical cyclosporine (CsA) and resulted in 88.9% of rejectionfree and statistically significant (=0.0465). In our study,topical steroid administration was also done and tapered off after six months. However, the systemic steroid was not given because of good compliance during treatment with topical steroids only and avoided the risk of systemic complication.Poor visual outcomes can be expected in infants, even with clear grafts. The time of suture removal can be lengthened based on age to reduce the risk of graft rejection and infection. Early refractive rehabilitation is initiated after suture removal following corneal transplantation as soon as possible. Spectacle correction or contact lenses are prescribed and changed as required by amblyopia therapy. Scheduled follow-ups must be monitored for good visual outcomes. In this study, patients were not given contact lenses due to the risk of falling off and difficulty being removed. Eye rehabilitation using spectacle correction and occlusion therapy might be saved and help to reduce the risk of amblyopia. The treatments were adjusted for the long term, following the improvement of visual outcomes. Additionally, we remove the suture quickly when it is loose to prevent secondary infection and rejection.One of the primary purposes of pediatric PK is to prevent visual loss from amblyopia and maintain a better visual outcome. A study by McClellanshowed that visual outcome after corneal transplantation is significantly worse in patients with CCO. Amblyopia associated with CCO is a critical determinant of final vision after surgery. Patients with better visual acuity outcomes or equal following to keratoplasty enable them to develop an ambulatory vision in the presence of amblyopia.

(1)设置一个循环控制变量来实现递减或递增1；(2)for语句圆括号内的3个表达式是可选的，都可以省略，但分号一定要保留。如果省略了条件表达式，那么默认为真；(3)可在一个for循环语句中提供用逗号分隔的表达式3和表达式1，但表达式2只能有一个；(4)for语句变量初始化部分声明的变量，其作用域只局限于for语句内部。

No consensus is available among studies to provide the optimal timing of keratoplasty. However, most studies found that infants (<5y) presented poorer graft survival than children aged 5-12y and aged 13-19y. Treatment of amblyopia is the most significant factor predictive of visual improvement postoperatively. On the contrary, complications can be prevented with frequent visits and cooperation between practitioners and patients. As mentioned in this study,the eldest age of the patient for surgery is 54mo, in which complication occurred 12mo later but showed improvement of visual acuity. Although the age gap of patients in this study had no significant difference that reflects the results (=0.52),the keratoplasty successfully delivered a clear graft in the first year. We believed that performing keratoplasty in infants early,especially in bilateral cases, may help improve and develop their visual acuity during that time. Further follow-up, close monitoring, and visual rehabilitation can reduce the severity of amblyopia in the future.

Graft rejection, ocular trauma on graft, and inflammation can occur as the complications of keratoplasty in children.Further post-operative failures such as cataracts can be caused by prolonged use of steroid medication. However,the formation of band keratopathy and scleromalacia are yet unknown in this study. Several theories are upsurged to understand pathogenesis. Band keratopathy may be related to renal liver dysfunction, increase serum calcium and phosphate, inflammation, or infection, and intracameral viscoelastic substance. As for scleromalacia, a metabolic disturbance may also play a role, such as rheumatoid arthritis and osteogenesis imperfecta. A recent study suggested the theoretical risk of corticosteroids to promote the thinning of the sclera.

Linhad conducted PK in children aged 0-7 years old with congenital corneal opacities. Results showed that ambulatory vision (≥20/960) was achieved in 43 of 60 eyes(71.7%) at the last follow-up, and 14 eyes (23.3%) had visual acuities >20/260. The ambulatory vision (=0.012) was achieved significantly higher in bilateral opacity eyes (88.5%)compared to unilateral opacity eyes (58.8%). There were no significant differences in visual acuity among the different follow-up subgroups (<12mo, 12-36mo, and >36mo after operation;=0.928). Ten of the 14 eyes that achieved 20/260 vision had corneal astigmatism ≤3.00 diopters.

The administration of antibiotic eyedrops was given hourly for the first week, then tapered off to six times daily for the next four weeks, followed by four times daily for five to six months. Frequent topical steroid is essential to reduce the high risk of rejection. The initial steroid eyedrops were added six times daily for the first four weeks, followed by slow tapered of four times daily for six months. Anti-glaucoma eyedrops were adjusted to administer topical steroids given the doses twice daily for four to six months.At each post‐operative visit in the office or under anesthesia,the examination of visual acuity and intraocular pressure (IOP)were measured. Additional slit-lamp handled was performed to assess the condition of the graft. The sutures were removed within four to six months after keratoplasty. Any loose sutures were removed immediately.

The major challenge of performing pediatric PK is the difficulty of obtaining clinical pre‐operative and post‐operative conditions to assess accurately since almost all the patients were uncooperative. Our study required long-term follow-up with closed monitoring, and we found this to be challenging.Amid the COVID-19 pandemic, patients avoid coming to the hospital recently, and monitoring was approached by phone call and photoshandphone.

Furthermore, an ultrasound biomicroscopy (UBM) and B-scan ultrasonography are usually required for evaluating the eye anterior and the posterior segments, including measurement of the axial diameter. Such evaluations can prevent the risk of graft failure after surgery. However, our study faced this limitation due to the absence of UBM in our clinic. Other reported studies showed that a comprehensive eye examination could predict the visual prognosis following PK. These include additional assessment and implementation of corneal transplants in children, including corneal, glaucoma, retina specialists, a pediatrician, and a geneticist. Further study associated with larger patients, advanced equipment, and different techniques is still needed to improve the outcomes of PK in infants and children.

In conclusion, pediatric PK is a challenge for corneal surgeons and pediatric ophthalmologist. The delayed procedure will affect the immaturity of the visual system that may lead to severe amblyopia. With a good survival at one year (83.3%)with 22mo of mean survival time, the visual acuity can be achieved (63%) and showed improvements (44%) during follow-up. The complications post pediatric PK are frequent,such as cataract, graft rejection and failure, band keratopathy and scleromalacia. Thus, the surgery on an infant or child requires careful case selection, adequate pre-operative evaluation, skilled surgery for optical correction, very close cooperation family-physician, intensive post-operative care,and post-operative amblyopia management. This study’s limitation includes the absence of UBM and difficulty in evaluating endothelial cell density in children.

生物浮床是利用浮床作为载体在池塘水面种植具有特定功能且易于在水中生长的植物，其原理是利用浮床植物根部吸收、转化、吸附、滤过养殖系统中残留的氮、磷及有机物质转化成植物生长所需要的营养物质，从而达到净化水质和优化池塘生态系统的一种水体修复技术。同时，浮床植物根部形成的“泌氧与耗氧”环境是微生物生长繁殖的良好场所，且使得整个池塘养殖系统中微生物菌群的结构与功能多样性得到有效调节。其中，浮床植物的选择是浮床池塘养殖建立的关键性因素。

The authors thank all the worker staff who contributed to this study and their support for elaborating the data.

3)经济发展程度：一个地区或区域的经济发展情况直接影响了部分电能替代技术的推广应用。例如电动汽车的充电设施配套设置建设以及公路发达程度等都会影响电动汽车的广泛推广应用。

在本文中，对地理信息系统在测绘中的运用与技术进行研究和分析，主要是从地理信息系统概述展开，随着现代社会经济和建筑行业不断发展，测绘工作有效开展也直接影响到后期工程项目顺利实施和最终工程质量，地理信息系统因其自身优势被广泛应用到测绘工作当中，为确保测绘数据可以更好满足实际工程建设需求，就需要充分借助地理信息系统应用优势和功能，使之为测绘测量工程提供有力技术支撑，保障和提高测绘工作效率和精准性。

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