International Study of Childhood Glaucoma

In partnership with the

International Study of Childhood Glaucoma Maria Papadopoulos, MB BS, FRCOphth,1 Elizabeth A. Vanner, MS, PhD,2 Alana L. Grajewski, MD,2 on behalf of the International Study of Childhood Glaucoma e Childhood Glaucoma Research Network (CGRN) Study Group* Purpose: To ascertain the types of childhood glaucoma managed at major international centers, current clinical practice, and intraocular pressure (IOP) control and visual acuity (VA) outcomes. Design: Prospective, multicenter, consecutive case series. Participants: All children with newly diagnosed glaucoma in at least 1 eye who fulfilled the Childhood Glaucoma Research Network (CGRN) definition of childhood glaucoma were recruited over a 1-year period with the aim of 18 months follow up. Methods: Demographic, clinical, management data (including complications), and outcomes (IOP and VA) were entered in a secure online database. All cases included in the outcome analysis had a minimum of 6 months follow-up. Main Outcome Measures: The management of childhood glaucoma, IOP control, and VA outcomes. Results: A total of 441 children (691 eyes) with newly diagnosed glaucoma were enrolled from 17 international centers. Approximately 60% of patients came from 2 centers in India; however, 47.5% of Indian patients had no or less than 6 months of follow-up outcome data from diagnosis. Primary congenital glaucoma (PCG) was the most common diagnosis (45.4%, n ¼ 314 eyes). There was a statistically significant association between diagnosis and ethnicity/race (P < 0.001), with PCG more frequent in nonwhite patients, glaucoma associated with acquired conditions more frequent in South Asian patients, and glaucoma after cataract surgery more frequent in white patients. The initial surgical procedure of choice for eyes with PCG significantly differed by country. Angle surgery alone was first line in centers in the United States, United Kingdom, Germany, Saudi Arabia, Singapore, and Israel (Group 1), whereas combined trabeculotomy-trabeculectomy was the first-line procedure for PCG in centers in India and Ghana (Group 2). There was no significant difference in IOP control nor VA between the 2 groups. Conclusions: The most common diagnoses in this international study of children with newly diagnosed glaucoma in order of frequency were PCG, glaucoma after congenital idiopathic cataract surgery, and glaucoma associated with trauma. Indian children had a disproportionately high loss to follow-up rate. Despite international differences in the surgical approach to PCG, there was no statistically significant difference in IOP or VA outcomes. We hope the results of this study will inform key areas of future international, collaborative clinical research in childhood glaucoma. Ophthalmology Glaucoma 2020;-:1e13 ª 2020 by the American Academy of Ophthalmology

Childhood glaucoma is characterized by elevated intraocular pressure (IOP)-related damage to the eye and is caused by a diverse group of conditions.1,2 The successful control of IOP is crucial in the management of this condition along with ametropia correction and amblyopia treatment to optimize long-term visual outcomes. Medical therapy plays an important role in controlling IOP, but surgery is often inevitable especially for those with primary congenital glaucoma (PCG), for whom angle surgery is often first line.3e5 However, for many reasons, internationally there are diverse surgical approaches to childhood glaucoma. Important considerations for the surgical procedure of choice include the type and severity of glaucoma, the age of onset, the corneal clarity, and the surgeon’s training and experience. Furthermore, there are individual population challenges such as socioeconomic factors that affect the local availability of devices and the patient's ability to attend  2020 by the American Academy of Ophthalmology Published by Elsevier Inc.

ongoing care. The paucity of randomized surgical trials in childhood glaucoma to inform decision-making also compounds the problem. This variation in worldwide practice was highlighted by the results of a surgical survey of experts in the field in 2013, as part of a World Glaucoma Associationesponsored consensus in childhood glaucoma.6 Responses from 78 ophthalmologists about their preferred first-line surgical intervention for the most common childhood glaucoma conditions were diverse, especially with regard to secondary childhood glaucoma. In light of this, the Childhood Glaucoma Research Network (CGRN), an international organization composed of clinicians and scientists who specialize in treating children with glaucoma, established an internet registry for children with newly diagnosed glaucoma at major international centers that manage childhood glaucoma. The aim

https://doi.org/10.1016/j.ogla.2019.12.007 ISSN 2589-4196/20

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was to ascertain the types of childhood glaucoma they manage, existing clinical practice, identification of any national and international differences, and IOP and visual acuity (VA) outcomes.

Methods Investigators from all continents were invited to participate and chosen on the basis of their experience of managing children with glaucoma and publishing within the field. Investigators from each participating center were asked to record, over a 1year period, consecutively any child (<18 years of age) with newly diagnosed glaucoma in at least 1 eye who fulfilled the CGRN definition of childhood glaucoma, which has been internationally validated and adopted by the American Board of Ophthalmology.1 Exclusion criteria were children with a preexisting diagnosis of glaucoma and glaucoma suspects, including those with ocular hypertension. Each center was required to obtain Institutional Review Board (or equivalent) approval and parental/caregiver consent when required. The enrollment of patients commenced for the majority of centers on May 20, 2013, with exceptions noted in study group information. The study adhered to the tenets of the Declaration of Helsinki.

Baseline Data Investigators entered baseline data online detailing (1) demographic data including birth year (and sometimes birth month and day when allowed), gender, country of residence, public or private pay, ethnicity, consanguinity, and family history of childhood-onset glaucoma; (2) clinical data including diagnosis as per the CGRN classification,1,2 laterality, VA and method of testing, lens status (clear, cataract, aphakia, pseudophakia), IOP measurement, medications, tonometer, details of examination under anesthesia (EUA), where applicable; and (3) management data around the time of diagnosis, including medication, laser, and surgery. Ethnic and racial groups were based on a modified UK Office for National statistics taxonomy with the addition of ethnicities represented in the studied populations, for example, Hispanic or Latino, after consultation with investigators. Best-corrected quantitative VA was translated to its logarithm of the minimum angle of resolution (logMAR) equivalent VA. If VA assessment was not possible or not performed, then it was documented as not recorded and logMAR VA was classified as missing. Certain nonquantitative visual acuities were assigned the following logMAR VA: count fingers ¼ 2.10; hand motions ¼ 2.40, perception of light ¼ 2.70, and no perception of light ¼ 3.00.7 Combination drops were recorded as 2 separate medications. Patient age at baseline was calculated only for those patients who had complete birth year, month, and day data.

Management Data All medical, laser, and incisional surgical interventions (glaucoma and nonglaucoma) and any complications related to surgery were to be recorded as they occurred over the 18-month followup period. When surgical interventions, dates, and management details were unclear or when “other” was selected for diagnosis or surgical intervention, investigators were contacted for clarification.

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Outcome Measures Investigators were asked to enter data on IOP control, including medications and VA at 6, 12, and 18 months from the baseline visit. Multiple reminders were sent to investigators throughout the 18-month follow-up period to encourage completion of outcome data. However, because investigators were allowed to practice their standard patient care, there was significant variability in the timings of follow-up and in outcome data entry. Only 8.8% (n ¼ 39) of patients had outcome measures recorded within all the requested 3 time points. In light of this and to maximize outcome data, all cases with a minimum of 6 months of follow-up data were analyzed. Poor follow-up was defined as there being no or less than 6 months of follow-up outcome data from baseline assessment. As IOP measurement accuracy is potentially influenced by numerous factors in children, including inhalational anesthesia that reduces IOP, the investigator was also asked to comment as to whether he/she thought IOP was clinically controlled as determined by the whole clinical scenario, taking into account, for example, corneal clarity and stability of ocular dimensions. Success was defined numerically as an IOP 21 mmHg without (complete success) or with (qualified success) medications and clinically, as defined above.

Data Entry The online data-collection software and website were specifically developed using open source software (OpenEyes) at Moorfields Eye Hospital. The data fields were based on the template of the BIG Eye study.4 We used a forced answer method of data collection, but some data fields, namely, diagnosis, surgery, and complication, had an “other” option associated with free text. The option of “unknown” was available for consanguinity, family history of glaucoma, diagnosis, and VA method. All data fields had to be completed before it was possible to save an entry. We validated the data fields with 3 test cases completed by investigators before commencement of the study. Data were entered on a password-protected, secure website through an SSL-encrypted connection and stored in a secure SQL-server database. A universally unique identifier was generated for each patient. The data were anonymized as required by the NHS code of Practice on Confidentiality and was compatible with the Health Insurance Portability and Accountability Act guidelines in the United States. The Glaucoma Research Network at the Wilmer Eye Institute served as the coordinating center to which all data were sent and stored. The Samuel & Ethel Balkan International Pediatric Glaucoma Center at Bascom Palmer Eye Institute provided biostatistical support.

Statistical Methods Categoric variables were summarized with numbers and percentages, and continuous variables were summarized with means and standard deviations (SDs). Differences between categoric variables were assessed using chi-square, Fisher exact, or exact chi-square tests, as appropriate. Differences between continuous variables were assessed using t tests and analysis of variance when parametric statistics were appropriate and using ManneWhitney Wilcoxon and paired Wilcoxon tests when nonparametric statistics were appropriate. Treatment success was evaluated by KaplaneMeier life-table analysis and Cox proportional hazards regression analysis, which accounted for the correlation between

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International Study of Childhood Glaucoma 2 centers in the United Kingdom, with a disproportionately low rate of poor follow-up of just 1 patient (2.9%).

Demographics Ethnicity/Race Patients’ major and minor ethnicity/race groups are shown in Table 2. With regard to ethnicity/race and diagnosis, PCG was the most common diagnosis for the major ethnic groups (Fig 2). A statistically significant association between ethnicity/race and diagnosis was found (P < 0.001, chisquare test), with PCG more frequent in nonwhite patients. Glaucoma was associated with acquired conditions more frequently in South Asian patients, and glaucoma after cataract surgery was more frequent in white patients. Gender and Age

Figure 1. Flowchart showing patient enrollment and analysis.

both eyes of the patients with bilateral glaucoma. All analyses were performed using SAS version 9.4 (SAS Institute Inc, Cary, NC). P  0.05 was considered statistically significant.

More males presented with PCG (58.4%) than females (Table 2). The percentage of males (33.3%) and females (31.1%) who had poor follow-up was similar. Of the 171 patients with PCG for whom age could be calculated, 37.4% (n ¼ 64) were seen by 3 months of age, 60.2% (n ¼ 103) were seen by 6 months, 71.4% (n ¼ 122) were seen by 1 year, and 78.4% (n ¼ 134) were seen by 2 years. For patients with PCG, the mean age at baseline was 1.7 years, with an SD of 2.8 years (5-number summary: minimum ¼ 0.0, 25th percentile ¼ 0.1, median ¼ 0.4, 75th percentile ¼ 1.3, maximum ¼ 13.5 years). The age at baseline for patients with PCG did not differ significantly by ethnicity (P ¼ 0.53, analysis of variance), with a mean age of 1.1 years for white and black patients, 1.8 years for South Asian patients, and 2.1 years for other ethnicities. For patients with secondary glaucoma, the mean age at baseline was 6.4 years, with an SD of 5.1 years (5-number summary: 0.0, 0.6, 6.2, 11.0, 16.8 years). Family History of Glaucoma and Consanguinity

Results

Approximately 10% of all patients had a family history of childhood-onset glaucoma and a history of consanguinity, but for most, this was unknown (Table 2).

Participating Centers: Patient Numbers and Follow-up

Health Insurance

Initially, 572 children were entered into the database, of whom 131 were excluded (Fig 1). A total of 441 patients (250 with bilateral glaucoma and 191 with unilateral glaucoma), resulting in 691 eyes, met the inclusion criteria of newly diagnosed glaucoma enrolled in 8 countries (17 centers) over a 1-year period (Table 1). Approximately 60% of enrolled patients (n ¼ 261) came from 1 of the 2 centers in India, but had disproportionately poor follow-up of 47.5% (n ¼ 124) (i.e., no follow-up or < 6 months of follow-up outcome data from baseline assessment) compared with other countries combined (10.6%; n ¼ 19). In contrast, approximately one-quarter of the patients (n ¼ 106) were seen at 1 of the 8 centers in the United States, and only 11.3% (n ¼ 12) had poor follow-up. Approximately less than 8% of the patients (n ¼ 35) were seen at 1 of the

Overall, 50% of patients had no public or private healthcare coverage (Table 2). More than three-quarters of patients with poor follow-up had no healthcare coverage (n ¼ 113, 79.0%) as opposed to only 5.6% (n ¼ 8) with public healthcare coverage. Diagnosis The majority of the eyes had primary childhood glaucoma (n ¼ 367, 53.1%), of which 314 eyes had PCG (45.4%) and 53 eyes had juvenile open-angle glaucoma (JOAG) (7.7%) (Table 3). The most common cause of secondary childhood glaucoma was glaucoma after congenital idiopathic cataract surgery in 43 eyes (6.2%), followed

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Table 1. List of Centers

Lens Status

All Patients PCG Patients n (%) India Lakshmi Vara (LV) Prasad Eye Institute Aravind Eye Hospital United States Vanderbilt Eye Institute Duke University Hospital Bascom Palmer Eye Institute Children’s Hospital of Pittsburgh Emory University Hospital University of California Davis Medical Centre University of Minnesota Jules Stein Eye Institute United Kingdom Moorfields Eye Hospital Birmingham & Midland Eye Centre Saudi Arabia King Khaled Eye Specialist Hospital Ghana Korle-Bu Teaching Hospital University of Ghana Singapore Singapore National Eye Centre Israel Carmel Medical Center Germany University Wurzburg Total

261 197 64 106 27 23 18 12 10 9

(59.2%) (44.7%) (14.5%) (24.0%) (5.9%) (5.2%) (4.1%) (2.7%) (2.3%) (2.0%)

7 (1.6%) 1 (0.2%) 35 (8.0%) 33 (7.5%) 2 (0.5%)

n (%) 121 100 21 33 6 4 9 1 5 5

(63.7%) (52.6%) (11.1%) (17.3%) (3.2%) (2.1%) (4.7%) (0.5%) (2.6%) (2.6%)

2 1 10 10 0

(1.1%) (0.5%) (5.3%) (5.3%) (0.0%)

10 (2.3%)

9 (4.7%)

9 (2.0%)

7 (3.7%)

9 (2.0%)

1 (0.5%)

7 (1.6%)

6 (3.2%)

4 (0.9%) 441

3 (1.6%) 190

PCG ¼ primary congenital glaucoma. n (n%) ¼ number and percent of total sample.

closely by glaucoma associated with trauma in 40 eyes (5.8%).

Baseline Clinical Assessment Visual Acuity Overall quantitative VA was possible in 48.1% and in only 20.5% of patients with PCG considering age at diagnosis (Table 4). Of the 314 eyes that had a quantitative VA at baseline (45.6% of total eyes), the overall mean VA was 1.06 logMAR (SD, 1.00) (Table 5). Intraocular Pressure Overall, applanation tonometry was the most common method for measuring IOP at 74.2% (Goldman 37.9% and Perkins 36.3%) (Table 4). Most patients with PCG had the baseline IOP measurement taken during an EUA (63.2%) with a Perkins tonometer (60.0%) under inhalational anesthesia (81.7%) followed by nitrous oxide, which, although an inhalational anesthetic, is thought to have a minimal effect on IOP (7.5%) and ketamine anesthesia (6.7%) (Table 4). At baseline, the mean IOP for all eyes was 26.9 mmHg with similar findings for both PCG and secondary glaucoma eyes (Table 5).

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At baseline, most eyes had clear lenses (n ¼ 551, 79.7%), followed by aphakia (n ¼ 78, 11.3%), cataract (n ¼ 46, 6.7%), and pseudophakia (n ¼ 16, 2.3%). Of the eyes with follow-up, 5 had cataract extraction surgery (3 eyes with clear lenses and 2 with cataracts at baseline).

Management Primary Congenital Glaucoma As PCG comprised the largest group of the cohort (314 of 691 eyes [45.4%]), its management was analyzed in detail. Some Table 2. Demographic Characteristics

Total Ethnicity/race White North American British European Any other white background Black Black African African American Black Caribbean Asian Indian Chinese Pakistani Bangladeshi Any other Asian background Middle Eastern Arabic Israeli Any other Middle Eastern background Hispanic or Latino American Indian or Alaska Native Mixed Other Gender Male Female Family history of childhood-onset glaucoma Yes No Unknown Consanguinity Yes No Unknown Healthcare coverage Public Private None

All Patients

PCG Patients

n (%)

n (%)

441

190

89 59 21 6 3 37 17 13 7 261 250 8 3 3 9 19 14 3 2

(20.3%) (13.4%) (4.8%) (1.4%) (0.7%) (8.5%) (3.9%) (3.0%) (1.6%) (59.2%) (56.7%) (1.8%) (0.7%) (0.7%) (2.0%) (4.4%) (3.2%) (0.7%) (0.5%)

15 1 5 2

(3.4%) (0.2%) (1.1%) (0.5%)

23 12 5 4 2 22 13 5 4 119 116 0 0 1 2 16 13 2 1 7 0 2 1

(12.1%) (6.3%) (2.6%) (2.1%) (1.1%) (11.5%) (6.8%) (2.6%) (2.1%) (62.7%) (61,1%) (0.0%) (0.0%) (0.5%) (1.1%) (8.4%) (6.8%) (1.1%) (0.5%) (3.7%) (0.0%) (1.1%) (0.5%)

261 (59.2%) 180 (40.8%)

111 (58.4%) 79 (41.6%)

41 (9.3%) 32 (7.3%) 368 (83.5%)

10 (5.3%) 17 (9.0%) 163 (85.8%)

43 (9.8%) 63 (14.3%) 335 (76.0%)

17 (9.0%) 44 (23.2%) 130 (67.9%)

105 (23.8%) 115 (26.1%) 221 (50.1%)

47 (24.7%) 30 (15.8%) 113 (59.5%)

PCG ¼ primary congenital glaucoma. n (n%) ¼ number and percent of total sample.

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Figure 2. Ethnic/racial groups and glaucoma diagnosis (n ¼ 441 patients). AC ¼ glaucoma associated with acquired condition; FCS ¼ glaucoma after cataract surgery; JOAG ¼ juvenile open-angle glaucoma; NAOA ¼ glaucoma associated with nonacquired ocular anomalies; NASDS ¼ glaucoma associated with nonacquired systemic disease; PCG ¼ primary congenital glaucoma; UNKN ¼ glaucoma cause unknown or other.

differences in surgical approach were noted according to location, which allowed us to group centers into Group 1 (United States, United Kingdom, Germany, Saudi Arabia, Singapore, and Israel) and Group 2 (India and Ghana). Of the 311 eyes with PCG (not including 3 eyes that were spontaneously arrested), 82.3% underwent surgery (n ¼ 256 eyes), 13.5% received medical treatment only (n ¼ 42 eyes), and 4.2% received no recorded treatment (n ¼ 13 eyes) (Table 6). A significantly higher percentage of eyes were treated medically only in Group 2 compared with Group 1 (16.9% vs. 6.1%, P < 0.001, chi-square test). Of the eyes that received surgery, 57.0% (146/256) had medication before surgery, and on average, 1.72 classes of medication were prescribed preoperatively (range, 1e5). Topical carbonic anhydrase inhibitor was the most common medication prescribed, followed by beta-blockers, prostaglandin analogues, alpha agonists, parasympathomimetics, and oral carbonic anhydrase inhibitors.

Surgery Surgery was performed within 7 days of the baseline visit in 72.7% (n ¼ 186 eyes), 14 days in 83.2% (n ¼ 213 eyes), and 28 days in 88.3% (n ¼ 226 eyes) (Table 6). Overall, the mean time from baseline visit to surgery was 17.8 days (SD, 51.7 days; median, 3 days; range, 0e380 days). The mean time from baseline visit to surgery was shorter in Group 2 at 13.4 days (SD, 43.8 days; median, 0 days; range, 0e380 days) versus 25.8 days in Group 1 (SD, 62.7 days; median, 8 days; range, 0e366 days), but the difference was not statistically significant (P ¼ 0.09, 2-sample t test). This indicates that for at least half of the eyes that had surgery in Group 2, the surgery occurred at the baseline visit.

Of the PCG eyes that had surgery, 83.6% had 1 glaucoma surgery only (Table 6). Of the 16.4% of eyes that underwent more than 1 glaucoma surgery; 13.3% underwent 2 operations, 2.7% underwent 3 operations, 0.0% underwent 4 operations, and 0.4% underwent 5 operations. For PCG eyes that underwent surgery, the initial surgical procedure of choice differed significantly by groups of centers (P < 0.001, exact chi-square). Angle surgery alone was first-line surgery in 88.0% (81/92 eyes, goniotomy 25.0%, conventional trabeculotomy 32.6%, 360 trabeculotomy 30.4%) for Group 1 followed by trabeculectomy in 8.7% (8/ 92), combined trabeculotomy-trabeculectomy (CTT) in 2.2% (2/92), and transscleral diode in 1.1% (1/92) (Fig 3, Table 7). In these countries, 75.0% of trabeculectomies (6/8) were performed with the antimetabolite mitomycin C (MMC) 0.4 mg/ml, and 50.0% of CTT (1/2) were performed with MMC 0.4 mg/ml. Combined trabeculotomy-trabeculectomy (79.3%, 130/164) was the most common first-line procedure for PCG in Group 2 followed by trabeculectomy in 16.5% (27/164) and transscleral diode in 4.3% (7/164). In these countries, only 6.9% of CTT surgeries (9/130) and 29.6% of trabeculectomies (8/27) were performed with MMC (0.2e0.4 mg/ml) or no MMC dosage was recorded (Fig 3, Table 7). Primary glaucoma drainage device (GDD) surgery was not first-line surgery for any PCG eyes. For Group 1, of the 35 eyes that had more than 1 glaucoma procedure, most underwent GDD surgery (n ¼ 16, 45.7%: Ahmed 184; [n ¼ 9, 25.7%]; Ahmed 96, [n ¼ 4, 11.4%]; Baerveldt 350, [n ¼ 3, 8.6%]) followed by goniotomy (n ¼ 10, 28.6%), conventional trabeculotomy (n ¼ 2, 5.7%), trabeculectomy (n ¼ 2, 5.7%), transscleral diode (n ¼ 2, 5.7%), deep sclerectomy (n ¼ 2, 5.7%), and bleb needling (n ¼ 1, 2.9%). For Group 2, the 7 eyes that underwent more than 1 glaucoma procedure had trabeculectomy (n ¼ 3, 42.9%), GDD surgery (Aurolab

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Table 3. Diagnosis of Childhood Glaucoma n (%) Primary Childhood Glaucoma Primary Congenital Glaucoma Neonatal or newborn onset (0e1 mos) Infantile onset (>1e24 mos) Late onset or late recognized (>2 yrs) Spontaneously arrested (normal IOP but typical signs of PCG) Juvenile Open-Angle Glaucoma Secondary Childhood Glaucoma Glaucoma Associated with Nonacquired Ocular Anomalies Aniridia AxenfeldeRieger anomaly/syndrome Peters Anomaly Microspherophakia (phakic/aphakic) Microphthalmos Microcornea Neovascular glaucoma (FEVR) Ectropion uveae Congenital iris hypoplasia Posterior polymorphous dystrophy Oculodermal melanocytosis (Nevus of Ota) Glaucoma Associated with Nonacquired Systemic Disease or Syndrome Phacomatoses: SturgeeWeber syndrome Chromosomal disorders Cutis marmorata telangiectasia congenita Stickler syndrome Homocysteinuria Lowe syndrome Phacomatoses: Neurofibromatosis Ehler Danlos Marfan syndrome Phacomatoses: Klippel-Trenaunay-Weber syndrome Glaucoma Associated with Acquired Condition Trauma Steroid induced Uveitis Retinopathy of prematurity Neovascular glaucoma Postsurgery other than cataract surgery Iris cysts Keratoconus Retinal dystrophy Glaucoma after Cataract Surgery Congenital idiopathic cataract Congenital cataract associated with ocular anomalies/systemic disease (no previous glaucoma) Acquired cataract (no previous glaucoma) Glaucoma Cause Unknown/Other Glaucoma cause unknown Angle-closure glaucoma Total

n (%)

n (%)

367 (53.1%) 314 (45.4%) 107 147 57 3

(15.5%) (21.3%) (8.3%) (0.4%)

27 19 13 8 7 6 4 3 2 2 1

(3.9%) (2.8%) (1.9%) (1.2%) (1.0%) (0.9%) (0.6%) (0.4%) (0.3%) (0.3%) (0.1%)

23 16 3 2 2 2 2 2 1 1

(3.3%) (2.3%) (0.4%) (0.3%) (0.3%) (0.3%) (0.3%) (0.3%) (0.1%) (0.1%)

40 27 15 13 5 3 2 2 2

(5.8%) (3.9%) (2.2%) (1.9%) (0.7%) (0.4%) (0.3%) (0.3%) (0.3%)

53 (7.7%) 315 (45.6%) 92 (13.3%)

54 (7.8%)

109 (15.8%)

60 (8.7%) 43 (6.2%) 11 (1.6%) 6 (0.9%) 9 (1.3%) 7 (1.0%) 2 (0.3%) 691 eyes

FEVR ¼ familial exudative vitreoretinopathy; IOP ¼ intraocular pressure; PCG ¼ primary congenital glaucoma. n (%) ¼ number (percent of total eyes).

aqueous drainage implant n ¼ 3, 42.9%), and bleb needling (n ¼ 1, 14.3%).

Complications Only 0.8% of PCG eyes (2/256 eyes) were reported to have surgical complications, all of which required surgery. One eye, after conventional trabeculotomy, required an Ahmed

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implant (184) that required tube shortening and repositioning because of corneal-tube touch. The second eye, after conventional trabeculotomy, required revision for an inadvertent bleb and anterior chamber reformation for hypotony and choroidal detachment. Both of these cases, which required surgery for complications, were originally listed under surgical management, but were subsequently considered as surgery for complications after confirmation from the investigators.

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Table 4. Visual Acuity Assessment Methods, Tonometers, and Examination Under Anesthesia Agents At Baseline

Total cases VA assessment methods No quantitative VA Snellen feet Snellen meter Keeler/Teller acuity cards Cardiff cards Allen pictures HOTV logMAR Crowded Kay pictures Uncrowded Kay pictures Other Tonometers Goldmann Perkins Icare Tonopen Pneumotonometry Schiotz EUA agents No Inhalational Nitrous oxide Ketamine Chloral hydrate Benzodiazepine

All Patients

PCG Patients

441

190

229 123 58 8 7 6 4 4 0 0 2

(51.9%) (27.9%) (13.2%) (1.8%) (1.6%) (1.4%) (0.9%) (0.9%) (0.0%) (0.0%) (0.5%)

151 21 5 5 4 1 1 0 0 0 2

(79.5%) (11.1%) (2.6%) (2.6%) (2.1%) (0.5%) (0.5%) (0.0%) (0.0%) (0.0%) (1.1%)

167 160 61 44 8 1

(37.9%) (36.3%) (13.8%) (10.0%) (1.8%) (0.2%)

22 114 26 21 6 1

(11.6%) (60.0%) (13.7%) (11.1%) (3.2%) (0.5%)

277 125 18 13 6 2

(62.8%) (28.3%) (4.1%) (3.0%) (1.4%) (0.5%)

70 98 9 8 3 2

(36.8%) (51.6%) (4.7%) (4.2%) (1.6%) (1.1%)

EUA ¼ examination under anesthesia; logMAR ¼ logarithm of the minimum angle of resolution; PCG ¼ primary congenital glaucoma; VA ¼ visual acuity.

(n ¼ 2), GDD surgery (n ¼ 1), and transscleral diode (n ¼ 1). Group 2 underwent trabeculectomy as the initial approach (n ¼ 9), followed by angle surgery (n ¼ 1). Secondary Childhood Glaucoma Secondary childhood glaucoma was found most commonly in eyes after surgery for congenital idiopathic cataract, for which management data were available for 83.7% of eyes (n ¼ 36/43 eyes). Glaucoma surgery was necessary in 41.7% (15/36 eyes), with the most common approach being diode (33.3%), angle surgery (26.7%), GDD surgery (26.7%), CTT (6.7%), and trabeculectomy (6.7%). Trauma was the next most common cause of secondary childhood glaucoma, for which follow-up data were available for 90% of eyes (n ¼ 36/40 eyes). Only 4 eyes underwent surgery (11.1%), and the approach was highly variable with 1 eye each receiving angle surgery, trabeculectomy, GDD surgery, and diode. For aniridia, 77.8% (n ¼ 21/27 eyes) had follow-up data revealing the need for surgery in 42.9% (9/21), namely, CTT (44.4%), diode (33.3%), and trabeculectomy (22.2%). Eyes with steroid-induced glaucoma had follow-up data in 88.9% (n ¼ 24/27 eyes), of which 41.7% required surgery (10/24 eyes), mainly trabeculectomy (90%) followed by angle surgery (10%). Glaucoma associated with SturgeeWeber syndrome had follow-up data in 87% (n ¼ 20/23), revealing surgery in the majority (55%), with angle surgery the most common approach (63.6%) followed by CTT (18.1%) and trabeculectomy (18.1%). Of the 19 eyes with the diagnosis of AxenfeldeRieger anomaly/syndrome, 15 had available management data (78.9%), of which one-third required surgery during the follow-up period, namely, CTT (40%), diode (40%), and trabeculectomy (10%).

Outcomes

Juvenile Open-Angle Glaucoma There were 53 eyes with JOAG, of which 47 (88.7%) had management data recorded. Glaucoma surgery was performed in 42.6% (n ¼ 20), and again the approach differed according to location, with Group 1 favoring angle surgery as the initial approach (n ¼ 6) followed by trabeculectomy

Of the 691 eyes enrolled, 470 (68.0%) had follow-up data of 6 months (excluding spontaneously arrested PCG eyes) and were analyzed for the outcomes described next. Visual acuity outcomes are based on quantitative VA where available at baseline and final visit.

Table 5. Baseline and Final Visit Quantitative Visual Acuity and Intraocular Pressure Eyes with ‡ 6 Mos Follow-up Baseline Data for All Eyes

IOP (mmHg) Mean SD VA (logMAR) Mean SD

All Childhood Glaucoma Eyes

Primary Congenital Glaucoma Eyes

Secondary Glaucoma Eyes

n ¼ 691 26.9 9.6 n ¼ 314 1.06 1.00

n ¼ 314 27.5 8.0 n ¼ 57 1.31 0.90

n ¼ 315 26.1 10.7 n ¼ 199 1.12 1.02

Baseline Data

Final Visit

All Childhood Glaucoma Eyes

Primary Congenital Glaucoma Eyes

Secondary Glaucoma Eyes

n ¼ 470 26.7 9.3 n ¼ 213 0.82 0.88

n ¼ 203 28.2 8.1 n ¼ 32 1.21 0.82

n ¼ 217 25.4 10.1 n ¼ 133 0.79 0.86

All Childhood Glaucoma Eyes

Primary Congenital Glaucoma Eyes

Secondary Glaucoma Eyes

n ¼ 470 17.0 7.5 n ¼ 210 0.63 0.79

n ¼ 203 16.2 7.3 n ¼ 47 0.80 0.78

n ¼ 217 17.7 8.1 n ¼ 125 0.66 0.81

IOP ¼ intraocular pressure; logMAR ¼ logarithm of the minimum angle of resolution; SD ¼ standard deviation; VA ¼ visual acuity.

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Table 6. Management of Primary Congenital Glaucoma Eyes (n ¼ 311, Excluding Spontaneously Arrested Cases) All

Surgery Medication/no surgery No treatment recorded Total eyes Eyes treated with medication before surgery No. of medications before surgery Mean SD Types of medication before surgery* Beta-blocker Prostaglandin analogue Alpha agonist Parasympathomimetic Topical CAI Oral CAI Days from baseline visit to first surgery Up to 2 wks Up to 2 wks Up to 4 wks Mean SD No. of glaucoma surgeries per eye 1 2 3 4 5 Mean SD Eyes with at least 6 mos of follow-up No. of glaucoma surgeries per eye for eyes with at least 6 mos of follow-up 1 2 3 4 5 Mean SD

Group 1

Group 2

No.

%

No.

%

No.

%

256 42 13 311 146

82.3% 13.5% 4.2%

92 6 0 98 53

93.9% 6.1% 0.0%

164 36 13 213 93

77.0% 16.9% 6.1%

57.0%

1.72 0.89

57.6%

2.15 0.84

56.7%

1.47 0.82

73 32 16 6 120 4

50.0% 21.9% 11.0% 4.1% 82.2% 2.7%

41 21 8 4 40 0

77.4% 39.6% 15.1% 7.6% 75.5% 0.0%

186 213 226 17.83 51.65

72.7% 83.2% 88.3%

62 73 76 25.82 62.72

67.4% 79.4% 82.6%

124 140 150 13.35 43.83

75.6% 85.4% 91.5%

214 34 7 0 1 1.20 0.51 203

83.6% 13.3% 2.7% 0.0% 0.4%

62.0% 31.5% 5.4% 0.0% 1.1%

92.8%

157 5 2 0 0 1.06 0.28 113

95.7% 3.1% 1.2% 0.0% 0.0%

69.1%

57 29 5 0 1 1.47 0.70 90

148 34 7 0 1

77.9% 17.9% 3.7% 0.0% 0.5%

51 29 5 0 1

59.3% 33.7% 5.8% 0.0% 1.2%

1.27 0.58

1.50 0.72

32 11 8 2 80 4

34.4% 11.8% 8.6% 2.2% 86.0% 4.3%

57.4%

97 5 2 0 0

93.3% 4.8% 1.9% 0.0% 0.0% 1.09 0.34

CAI ¼ carbonic anhydrase inhibitor; SD ¼ standard deviation. Group 1: United States, United Kingdom, Germany, Saudi Arabia, Singapore, and Israel. Group 2: India and Ghana. *Some eyes had > 1 type of medication before surgery, so the percentages may total more than 100%.

Visual Acuity When assessing only eyes with both baseline and follow-up quantitative VA, there was a significant improvement in mean quantitative VA from baseline compared with final visit for the group overall (mean logMAR VA improvement ¼ 0.17, 95% confidence interval [CI], 0.09e0.24; P < 0.001, paired t test). This improvement was statistically significant for eyes with both PCG (n ¼ 24; mean logMAR VA improvement ¼ 0.38, 95% CI, 0.15e0.61; P < 0.001, Wilcoxon signed-rank test) and secondary glaucoma (n ¼ 111, mean logMAR VA improvement ¼ 0.12, 95% CI, 0.03e0.20; P ¼ 0.008, paired t test). The 0.26 difference in mean logMAR VA improvement between the eyes with PCG and secondary

8

glaucoma was statistically significant (P ¼ 0.009, ManneWhitney Wilcoxon test). For the 47 eyes (of 203 PCG eyes, 23.2%) with 6 months follow-up and final quantitative VA findings, 83% were without refractive correction (27/35 eyes, 77.2% in group 1 and 12/12 eyes, 100% in group 2) (Table 5). There was no statistically significant difference between the groups in mean final VA; however, only 38.9% of eyes in Group 1 and 10.6% in Group 2 had this outcome recorded. Intraocular Pressure Overall, 74.5% (350/470) of eyes with follow-up data for more than 6 months had successful control of IOP 21 mmHg (32.1% complete and 42.3% qualified success) and were

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Figure 3. Initial surgery for PCG eyes. Angle surgery ¼ goniotomy 25.0%, conventional trabeculotomy 32.6%, 360 trabeculotomy 30.4% in group 1: *CTT ¼ combined trabeculotomy-trabeculectomy. **Transscleral diode.

thought to be clinically controlled by the clinician (Table 8). Of the eyes that were unsuccessful, 25% had an IOP 21 mmHg and were not associated with clinical success possibly because of an inaccurate IOP measurement (e.g., with inhalational anesthesia). Conversely, 17.5% of unsuccessful cases had an IOP >21 mmHg and were

associated with clinical success. The median time to success was 7.8 months (95% CI, 7.0e9.1). Of the 190 PCG eyes with a history of surgery, 74.2% (141 of 190) were successful (complete 45.8% and qualified 28.4%) with a median time to success of 6.3 months (95% CI, 4.7e7.2). Group 1 (69/86 eyes) had a success of 80.2%

Table 7. Initial Surgery for Primary Congenital Glaucoma Eyes n (n%)

Angle Surgery

CTT

Group 1: United States, United Kingdom, Germany, Saudi Arabia, Singapore, and Israel Vanderbilt Eye Institute, United States 7 (87.5%) Duke University Hospital, United States 4 (66.7%) Bascom Palmer Eye Institute, United States 12 (100%) Children’s Hospital of Pittsburgh, United States 1 (100%) Emory University Hospital, United States 8 (100%) University of California Davis Medical 8 (88.9%) 1 (11.1%) Centre, United States University of Minnesota, United States 3 (100%) Jules Stein Eye Institute, United States 2 (100%) Moorfields Eye Hospital, United Kingdom 12 (100%) King Khaled Eye Hospital, Saudi Arabia 9 (60%) Singapore National Eye Centre, Singapore 2 (100%) Carmel Medical Center, Israel 9 (100%) University Wurzburg, Germany 5 (100%) Subtotal 81 (88%) 2 (2.2%) Group 2: India and Ghana Lakshmi Vara (LV) Prasad Eye Institute, India 106 (84.8%) Aravind Eye Hospital, India 11 (42.3%) Korle-Bu Teaching Hospital University of Ghana 13 (100%) Subtotal 130 (79.3%) Total

Trabeculectomy

Transscleral Diode 1 (12.5%)

2 (33.3%)

6 (40%)

8 (8.7%)

1 (1.1%)

15 (12%) 12 (46.2%)

4 (3.2%) 3 (11.5%)

27 (16.5%)

7 (4.3%)

Total 8 6 12 1 8 9 3 2 12 15 2 9 5 92 125 26 13 164 256

CTT ¼ combined trabeculotomy-trabeculectomy. n (n%) is the number and percent of surgeries at that center.

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Table 8. Intraocular Pressure Outcomes (Minimum 6-Month Follow-up) Childhood Glaucoma No. of eyes n (%) Complete success Qualified success Complete or qualified success Failure

151 199 350 120

470 (32.1%) (42.3%) (74.5%) (25.5%)

PCG 91 57 148 55

203 (44.8%) (28.1%) (72.9%) (27.1%)

JOAG 10 26 36 7

43 (23.3%) (60.5%) (83.7%) (16.3%)

Secondary Glaucoma 49 116 165 52

217 (22.6%) (53.5%) (76%) (24%)

PCG Surgery Group 1 42 27 69 17

86 (48.8%) (31.4%) (80.2%) (19.8%)

PCG Surgery Group 2 45 27 72 32

104 (43.3%) (26%) (69.2%) (30.8%)

JOAG ¼ juvenile open-angle glaucoma; PCG ¼ primary congenital glaucoma. Success was defined numerically as an IOP 21 mmHg without (complete success) or with (qualified success) medications and controlled clinically. PCG surgery Group 1 includes centers in the United States, the United Kingdom, Germany, Saudi Arabia, Singapore, and Israel; PCG surgery Group 2 includes centers in India and Ghana.

(complete 48.8% and qualified 31.4%) with a median time to success of 6.3 months (95% CI, 5.4e7.2). Group 2 (72/ 104 eyes) had a success of 69.2% (complete 43.3% and qualified 26%) with a median time to success of 4.7 months (95% CI, 2.6e12.5). Between the 2 groups, there were no statistically significant differences between success and failure (P ¼ 0.08, chi-square test), complete versus qualified success (P ¼ 0.84, chi-square test), or in time to success (hazard ratio, 1.22; 95% CI, 0.80e1.88; P ¼ 0.36, Cox regression). However, there was a statistically significant difference between the number of eyes in Group 1 undergoing just 1 operation (62.0%) compared with group 2 (95.7%) (P < 0.001, Fisher exact test), which persisted even when only eyes with least 6 months of follow-up were analyzed (Table 6). The successful eyes in Group 1 received a mean of 1.5 surgeries, whereas the successful eyes in Group 2 received a mean of 1.1 surgeries. This difference was statistically significant (P < 0.001, 2-sample t test). Of note, the mean follow-up time was statistically significantly shorter in Group 2 at 9.1 months (SD, 8.3 months; median, 7.0 months; range, 0e30.8 months) versus 15.5 months for Group 1 (SD, 5.8 months; median, 16.7 months; range, 2.8e28.1 months; P < 0.001, 2-sample t test). For JOAG, 83.7% (36/43 eyes) had successful IOP control (complete 23.3% and qualified 60.5%). For eyes with secondary glaucoma, 76.0% (165/217) had successful IOP control (complete 22.6% and qualified 53.3%) with a median time to success of 8.9 months (95% CI, 7.5e11.5). With regard to IOP reduction, for all eyes with greater than 6 months of follow-up, mean IOP reduced from 26.7 mmHg at baseline to 17.0 mmHg (mean IOP reduction ¼ 9.7 mmHg; 95% CI, 8.8e10.7; P < 0.001, paired t test). The PCG eyes had a mean IOP reduction of 12.0 mmHg (95% CI, 10.7e13.3, P < 0.001, paired t test), and eyes with secondary glaucoma had a mean IOP reduction of 7.7 mmHg (95% CI, 6.3e9.1; P < 0.001, paired t test). The 4.3 mmHg difference (95% CI, 2.4e6.2) in mean IOP reduction between the PCG eyes and secondary glaucoma eyes was statistically significant (P < 0.001, independent samples t test). In univariate analyses, of all the 470 eyes (68.0%) with greater than 6 months of follow-up, there was no significant association between achieving IOP control at the final visit and gender (P ¼ 0.36), time to first surgery from baseline (P ¼ 0.54), age at diagnosis (P ¼ 0.14), total number of

10

glaucoma surgeries (P ¼ 0.14), whether the eye received surgery (P ¼ 0.09), and which surgical procedure was performed (P ¼ 0.16). There were significant associations between achieving IOP control and ethnicity (P < 0.001) with eyes from white, Hispanic/Latino, and other races having a greater success rate than eyes from black, Asian, Middle Eastern, and mixed races and initial IOP (P ¼ 0.007), with successful eyes having a lower mean initial IOP. Similar results were found in analyses that included only the PCG eyes, except that in the PCG eyes, there was no significant association between achieving IOP control and initial IOP (P ¼ 0.67).

Discussion Childhood glaucoma is a potentially blinding disease associated with elevated IOP caused by a wide range of conditions. Successful control of IOP is essential for optimal visual outcomes and achieved by both medical and surgical therapy. Internationally, there is a diverse approach to childhood glaucoma, especially regarding the surgical procedure of choice that largely reflects the diverse nature of the conditions that cause it, the challenges of controlling the disease, especially geographic and racial influences, and the absence of controlled trials to inform decision-making. We established an internet registry for children newly diagnosed with glaucoma at major international centers to ascertain the types of childhood glaucoma they manage, existing clinical practice, and related IOP and VA outcomes. Over a 1-year enrollment period of newly diagnosed glaucoma in children from 17 international centers, we found PCG to be the most common diagnosis (45.4%), consistent with previous studies.3,4 The majority of patients with PCG came from 2 centers in India (63.7%), most likely reflecting the wide variation in the incidence of PCG, being particularly higher in populations where consanguinity is socially and culturally more acceptable.8e10 For example, the incidence in Great Britain has been reported at 1 in 18 500 live births4 as opposed to 1 in 3 300 live births in Southern India.11 Approximately 70% of patients with PCG presented by 1 year of age, similar to other reports.4,12 The mean age at diagnosis for white and black patients was 1.1 years, but older for South Asian patients at 1.8 years and other

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International Study of Childhood Glaucoma

ethnicities at 2.1 years, although this was not statistically significant. The mean age at presentation for whites and blacks is similar to that reported by other studies.4,13 Late presentation of the condition, usually in an advanced stage, in the South Asian population and generally in the developing world is a well-recognized challenge.14 Many factors contribute to this and include limited access to healthcare related to socioeconomic status, healthcare cost, physical distances needed to travel to healthcare centers, and potential financial impact to parents’ livelihoods. These factors also play a role in another common finding in the developing world of loss to follow-up that significantly affects the prognosis of children with an incurable, chronic condition such as glaucoma.14 In our study, approximately 50% of Indian patients had no or less than 6 months of follow-up data from diagnosis, and more than three-quarters of patients with poor follow-up had no healthcare coverage. In contrast, the United Kingdom, which has universal healthcare coverage, had only 2.9% of patients with poor follow-up. The numerous challenges faced in the developing world may explain why at least half of the PCG eyes that underwent surgery in India and Africa (Group 2) received it at the baseline visit, as opposed to within 8 days of the baseline visit for the other countries. Examining infants with glaucoma is known to be challenging. Approximately two-thirds of patients with PCG had the baseline IOP measurement taken during an EUA, most often with inhalational anesthesia (81.7%), despite its known association with IOP reduction.15,16 Ketamine anesthesia was used in only 6.7% of cases, although it is thought to result in IOP measurements that are commensurate with those taken in awake infants when given intravenously.16,17 The reluctance by anesthetists to use ketamine may be due to its potential for laryngospasm from increased oral secretions (reduced by atropine or glycopyrolate) and hallucinations (mitigated by midazolam).15 Primary congenital glaucoma is considered to be a surgical condition, and the traditional approach is angle surgery as first line either as goniotomy, trabeculotomy with a trabeculotome probe, or an illuminated microcatheter or other filament to achieve a 360-degree incision.18 However, primary CTT for PCG in certain ethnic populations who typically present late with a more severe phenotype (India19,20 and Middle East21,22) has been advocated because of a higher incidence of successful IOP control with a single operative procedure compared with trabeculotomy or trabeculectomy alone. However, more recently in a prospective study from India, circumferential trabeculotomy with an illuminated microcatheter achieved comparable results to primary CTT with MMC,23 but the high cost associated with a disposable illuminated microcatheter prohibits its widespread use in the developing world. In our study, the surgical approach to PCG was broadly divided along these lines with centers in the United States, the United Kingdom, Germany, Saudi Arabia, Singapore, and Israel (Group 1) preferring angle surgery alone (88.0%) as first-line treatment, almost evenly divided among goniotomy, conventional trabeculotomy, and circumferential trabeculotomy. Centers in India and Ghana (Group 2)

favored CTT (79.3%), with MMC use in approximately 7% of these cases. There was a statistically significant difference in the mean number of surgeries per eye between the 2 groups, with eyes from patients in Group 1 undergoing more operations than eyes from patients in Group 2. This persisted even when only eyes with 6 months of follow-up were analyzed (mean of 1.5 surgeries vs. mean of 1.1 surgeries). The mean follow-up time was significantly shorter in Group 2 at 9.1 months versus 15.5 months for Group 1. The approach to first-line therapy of PCG was different, as was the second procedure of choice. Approximately 50% of second glaucoma procedures in Group 1 were GDD surgery, whereas for Group 2 it was trabeculectomy in 50% of cases. Although this may change with the recent availability of a locally produced, cheaper GDD (Aurolab aqueous drainage implant) in India.24 The low rate of reported surgical complications was positive and may reflect the high incidence of angle surgery, known to be associated with low complications,25,26 underreporting, or an improvement in surgical techniques in dealing with these high-risk eyes.27 With regard to the outcome of IOP control, despite the difference in surgical approach for PCG between the 2 groups, there was no significant difference in IOP control with and without medications. However, more important when considering success of childhood glaucoma management is the VA outcome. Achieving the goal of preserving visual function in children with glaucoma is also influenced by factors other than IOP, such as corneal clarity, refractive status, and amblyopia, which also must be addressed. It was encouraging to find a statistically significant improvement in quantitative VA in PCG (albeit small number of eyes), but this was also the case in secondary glaucoma. The statistically significant difference in mean logMAR VA improvement of 0.26 between PCG eyes and eyes with secondary glaucoma may be due to the higher incidence of surgery for IOP control and associated improvement in corneal clarity. This higher rate of surgical intervention in PCG also likely explains the significantly greater mean IOP reduction difference between the 2 groups. Furthermore, the final quantitative VA was reported with refractive correction in only 17% of PCG eyes. The importance of ametropic correction (and amblyopia treatment) cannot be stressed enough if the child is to achieve his/her maximum visual potential. This is not to be underestimated, because better VA is associated with both higher functional visual ability and quality of life.28 With regard to other conditions, there was a high degree of overall success for JOAG (83.7%) and secondary glaucoma (76.0%), with more qualified than complete success, likely reflecting the greater use of medication as first-line therapy in these groups as opposed to surgery. Although the study was prospective and the investigators were asked to enter data on IOP control, including medications and VA at 6, 12, and 18 months from the baseline visit along with any interventions, investigators were allowed to practice their standard patient care, so there was significant variability in the timing of follow-up and the subsequent entry of outcome data. Accurately assessing the rate of complications was

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difficult because of the possibility of underreporting and case selection bias. Furthermore, the complications that were treated surgically were recorded as subsequent surgery rather than as complications, and had to be reclassified after consultation with the investigator. Loss to follow-up in certain centers was also a significant limitation of a study investigating a chronic condition such as glaucoma, with 31.5% (218/691 eyes) having less than 6 months of follow-up. Another limitation of the study was the dominance of 2 centers from India contributing approximately 60% of the patients enrolled. A strength of the design of the validated database was that all fields needed to be completed before a record could be saved, which greatly reduced the problem of missing data. With regard to analysis, although the Cox regression analysis does not completely adjust for bias introduced by fellow eye inclusion in bilateral cases, it provides superior results compared with alternatives that do not adjust for including both eyes of bilateral cases. Furthermore, because most publications in childhood glaucoma surgery are singlecenter or single-surgeon case series, a major strength of the study was the use of an internet registry with large-scale, multicenter, international collaboration. We hope that this study will facilitate and encourage the establishment of much-needed prospective, surgical trials in this field. However, we suggest that these trials use an internationally agreed definition of outcome success in children with glaucoma, which must include IOP control and VA, as well as ocular dimension stability, functional vision, and qualityof-life metrics when appropriate.28 Finally, in comparing different surgical interventions, of great value would be a validated childhood glaucoma severity score, which would take into account the numerous factors that potentially influence success, such as diagnosis, age of onset, ocular dimensions, media opacities, and amblyopia.29 In conclusion, in this multicenter, international study of children with newly diagnosed glaucoma, the most common glaucoma was PCG. Despite international differences in the surgical approach to PCG, there was no statistically significant difference in IOP or VA outcomes. We hope the results of this study will encourage future international, collaborative clinical research in childhood glaucoma. Acknowledgments. The authors thank Tami Frank supported by the CGRN and Trisha Horsmann from the University of Minnesota for administration duties; Bill Aylward and Jamie Neil from Moorfields Eye Hospital for developing the online data collection software and website; Michael Boland from the Glaucoma Research Network at Wilmer Eye Institute for managing data storage; and all the children, parents, and caregivers who took part in this study.

3. 4. 5. 6.

7.

8. 9.

10. 11. 12. 13. 14.

15.

16.

17.

18.

References 1. Beck A, Chang TCP, Freedman S. Definition, classification, differential diagnosis. In: Weinreb RN, Grajewski AL, Papadopoulos M, et al., eds. World Glaucoma Association (WGA) Consensus Series 9 - Childhood Glaucoma. Amsterdam: Kugler Publications; 2013:3e10. 2. Thau A, Lloyd M, Freedman S, et al. New classification system for pediatric glaucoma: implications for clinical care

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and a research registry. Curr Opin Ophthalmol. 2018;29: 385e394. Taylor RH, Ainsworth JR, Evans AR, Levin AV. The epidemiology of pediatric glaucoma: the Toronto experience. J AAPOS. 1999;3:308e315. Papadopoulos M, Cable N, Rahi J, Khaw PT. The British Infantile and Childhood Glaucoma (BIG) Eye Study. Invest Ophthalmol Vis Sci. 2007;48:4100e4106. Chen TC, Chen PP, Francis BA, et al. Pediatric glaucoma surgery: a report by the American Academy of Ophthalmology. Ophthalmology. 2014;121:2107e2115. Papadopoulos M, Edmunds B, Chiang M, et al. Glaucoma surgery in children. In: Weinreb RN, Grajewski AL, Papadopoulos M, et al., eds. World Glaucoma Association (WGA) Consensus Series 9 - Childhood Glaucoma. Amsterdam: Kugler Publications; 2013:96e134. Day AC, Donachie PH, Sparrow JM, et al. The Royal College of Ophthalmologists’ National Ophthalmology Database study of cataract surgery: report 1, visual outcomes and complications. Eye (Lond). 2015;29:552e560. Elder MJ. Congenital glaucoma in the West Bank and Gaza Strip. Br J Ophthalmol. 1993;77:413e416. Gencik A. Epidemiology and genetics of primary congenital glaucoma in Slovakia: description of a form of primary congenital glaucoma in gypsies with autosomal-recessive inheritance and complete penetrance. Dev Ophthalmol. 1989;16:76e115. Turacli ME, Aktan SG, Sayli BS, Akarsu N. Therapeutic and genetical aspects of congenital glaucomas. Int Ophthalmol. 1992;16:359e362. Dandona L, Williams JD, Williams BC, Rao GN. Populationbased assessment of childhood blindness in southern India. Arch Ophthalmol. 1998;116:545e546. Kolker AE, Hetherington Jr J. Congenital glaucoma. In: Becker-Shaffer’s Diagnosis and Therapy of the Glaucomas. 5th ed. St. Louis: CV Mosby; 1983:317e369. Barsoum-Homsy M, Chevrette L. Incidence and prognosis of childhood glaucoma: a study of 63 cases. Ophthalmology. 1986;93:1323e1327. Mandal A, Senthil S. Childhood glaucoma surgery in developing countries. In: Grajewski A, Bitrian E, Papadopoulos M, et al., eds. Surgical Management of Childhood Glaucoma. Switzerland: Springer; 2018:159e171. Tutiven JL, Kadarian-Baumgard D, Stein ALS. Anesthetic considerations in the evaluation of children with glaucoma. In: Grajewski A, Bitrian E, Papadopoulos M, et al., eds. Surgical Management of Childhood Glaucoma. Switzerland: Springer; 2018:9e35. Blumberg D, Congdon N, Jampel H, et al. The effects of sevoflurane and ketamine on intraocular pressure in children during examination under anesthesia. Am J Ophthalmol. 2007;143:494e949. Jones L, Sung V, Lascaratos G, et al. Intraocular pressure after ketamine and sevoflurane in children with glaucoma undergoing examination under anesthesia. Br J Ophthalmol. 2010;94:33e35. Edmunds B, Beck AD, Hoffman E, Grehn F. Angle surgery: Traculotomy. In: Grajewski A, Bitrian E, Papadopoulos M, et al., eds. Surgical Management of Childhood Glaucoma. Switzerland: Springer; 2018:57e78. Sood NN, Aggarwal HC, Kalra BR. Evaluation of surgery for congenital glaucoma. Indian J Ophthalmol. 1983;31: 609e611. Mandal AK, Gothwal VK, Nutheti R. Surgical outcome of primary developmental glaucoma: a single surgeon’s longterm experience from a tertiary eye care centre in India. Eye (Lond). 2007;21:764e774.

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21. Elder MJ. Combined trabeculotomy-trabeculectomy compared with primary trabeculectomy for congenital glaucoma. Br J Ophthalmol. 1994;78:745e748. 22. Al-Hazmi A, Awad A, Zwaan J, et al. Correlation between surgical success rate and severity of congenital glaucoma. Br J Ophthalmol. 2005;89:449e453. 23. Temkar S, Gupta S, Sihota R, et al. Illuminated microcatheter circumferential trabeculotomy versus combined trabeculotomy-trabeculectomy for primary congenital glaucoma: a randomized controlled trial. Am J Ophthalmol. 2015;159:490e497. 24. Kaushik S, Kataria P, Raj S, et al. Safety and efficacy of a lowcost glaucoma drainage device for refractory childhood glaucoma. Br J Ophthalmol. 2017;101:1623e1627. 25. Shaffer RN. Prognosis in primary infantile glaucoma (trabeculodysgenesis). In: Krieglstein GK, Leydhecker W, eds.

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Footnotes and Financial Disclosures Originally received: October 30, 2019. Final revision: December 22, 2019. Accepted: December 26, 2019. Available online: ---.

Manuscript no. 19-00089

1

Glaucoma Service, NIHR Biomedical Research Centre at Moorfields Eye Hospital and UCL Institute of Ophthalmology, London, United Kingdom. 2 Bascom Palmer Eye Institute, Miami, Florida. *The International Study of Childhood Glaucoma e CGRN Study Group: Arijit Mithra, Manju Pillai, Swati Upadhyaya, Ganesh Venkataraman (Aravind Eye Hospital, India); Ta Chen Peter Chang, Alana Grajewski, Elizabeth Hodapp (Bascom Palmer Eye Institute); Velota Sung (Birmingham and Midland Eye Centre, UK, commenced 6/8/13); Orna Geyer, Alvit Wolf (Carmel Medical Center, Israel commenced 6/3/14); Ellen Mitchell, Ken Nischal (Children’s Hospital of Pittsburgh); Sharon Freedman (Duke Eye Center); Allen Beck, Annette Giangiacomo (Emory Eye Center), Anne Coleman (Jules Stein Eye Institute); Arif Khan (King Khaled Eye Specialist Hospital, Saudi Arabia); Anil Mandal, Sirisha Senthil (Lakshmi Vara Prasad Eye Institute, India); John Brookes, Peng Tee Khaw, Maria Papadopoulos (Moorfields Eye Hospital, UK); Jocelyn Chua, Ching Lin Ho (Singapore National Eye Center, Singapore); James Brandt (University of California Davis Eye Center); Vera Essuman (Korle-Bu Teaching Hospital, Ghana, commenced 12/12/13); Ray Areaux, Elena Bitrian, Alana Grajewski (University of Minnesota); Franz Grehn, Thomas Klink (University Hospital Würzburg, Germany); Karen Joos (Vanderbilt Eye Institute). Financial Disclosure(s): The author(s) have made the following disclosure(s): M.P.: Financial support e UK Department of Health through the award made by the National Institute for Health Research to Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology for a Biomedical Research

Centre for Ophthalmology. Supported in part by the Moorfields Special Trustees and the OpenEyes Project which was funded by Moorfields Eye Hospital. The views expressed in this publication are those of the author and not necessarily those of the UK Department of Health. HUMAN SUBJECTS: Human subjects were included in this study. Institutional Review Board approval and parental/caregiver consent was obtained. All research adhered to the tenets of the Declaration of Helsinki. All participants provided informed consent when necessary. No animal subjects were used in this study. Author Contributions: Research design: Papadopoulos, Grajewski Data Collection: Papadopoulos, Grajewski Analysis and interpretation: Papadopoulos, Vanner, Grajewski Obtained funding: Papadopoulos Manuscript preparation: Papadopoulos, Vanner, Grajewski Abbreviations and Acronyms: CGRN ¼ Childhood Glaucoma Research Network; CI ¼ confidence interval; CTT ¼ combined trabeculotomy-trabeculectomy; EUA ¼ examination under anesthesia; GDD ¼ glaucoma drainage device; IOP ¼ intraocular pressure; JOAG ¼ juvenile open-angle glaucoma; logMAR ¼ logarithm of the minimum angle of resolution; MMC ¼ mitomycin C; PCG ¼ primary congenital glaucoma; SD ¼ standard deviation; VA ¼ visual acuity. Correspondence: Maria Papadopoulos, MB BS, FRCOphth, Glaucoma Service, Moorfields Eye Hospital, 162 City Road, London EC1V 2PD, UK. E-mail: maria [email protected].

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