Characteristics and long-term outcomes of childhood glaucoma: a retrospective-cohort study

Introduction

Childhood glaucoma is a vision-threatening disorder with an incidence of 2.29 to 5.41 per 100,000 individuals^1,2. The diagnosis of childhood glaucoma poses some challenges. This can be attributed to the variation in clinical presentations among different age groups. Despite high intraocular pressure (IOP) being the primary cause of glaucomatous damage, an accurate IOP measurement is not always obtained in children. Angle surgery is a common therapy but it is mostly associated with unfavourable outcomes in children, compared to that in adults³.

Childhood glaucoma encompasses several categories of glaucoma. The Childhood Glaucoma Research Network (CGRN) classification was proposed by an international consortium of glaucoma specialists in 2013 to standardise the definition of childhood glaucoma subtypes⁴. The prevalence of childhood glaucoma differs among ethnicities, ranging from 1:1,250 to 1:68,254 live births^5–12. The incidence and clinical characteristics of childhood glaucoma in Thailand have not yet been reported. The Queen Sirikit National Institute of Child Health is one of the largest tertiary centres in Thailand. It is responsible for the treatment of a majority of the complex paediatric cases from all over the country. Paediatric glaucoma clinics have been established by the joint collaboration between the Queen Sirikit National Institute of Child Health and the King Chulalongkorn Memorial Hospital, a university-based hospital. These clinics aimed to treat all paediatric glaucoma cases that were referred to the aforementioned hospitals and have been operated by the same group of glaucoma specialists for more than 10 years. We aimed to describe the clinical characteristics and brief long-term treatment outcomes of the large paediatric glaucoma cohorts of the two major referral centres in Thailand.

Methods

Results

The cohort comprised 423 patients (691 eyes). While 338 patients (532 eyes) were diagnosed with glaucoma, 85 patients (159 eyes) had GS. The average follow-up duration was 71.3±63.8 months (median 50; interquartile range, 22–112 months). Table 1 summarises the baseline characteristics. The average age at presentation was 3.91±4.40 years (median 1.58: interquartile range, 0.25–6.75 years). We recorded a family history of glaucoma in 15 (6.4%) patients. Furthermore, we found a statistically significant predominance of boys in all subjects (P=0.002), PCG (P=0.01), SCG-C (P=0.01), and GS (P=0.04). The mean of initial IOP was 28.5±11.2 mmHg. There was no difference in the initial IOP among the glaucoma subtypes (p=0.52). The most common presentation was cloudy eye (68.2%), which represented leukocoria or corneal haze, and megalocornea (14.5%). Table 2 demonstrates the mode of detection patterns and clinical presentations.

Most patients had bilateral glaucoma (63.4%). Among the 155 eyes of the unilateral cases, there were 72 (46.5%) and 83 (53.6%) right and left eyes, respectively. The diagnosis with significantly higher bilateral presentation included PCG (P=0.01), JOAG (P=0.03), SCG-O (P=0.03), and GS (P<0.001). SCG-S (unilateral 59.4%) and SCG-A (unilateral 53.6%) comprised a higher proportion of unilateral cases. However, the difference was statistically insignificant.

SCG-O was the most common subtype, accounting for 23% of the cohort or 29% of the glaucoma cases. In contrast, JOAG was the least common subtype. Figure 1 depicts the frequency of each glaucoma diagnosis.

Figure 1. Subtypes of childhood glaucoma.

PCG, primary congenital glaucoma; JOAG, juvenile open angle glaucoma; SCG-C, secondary glaucoma following cataract surgery; SCG-S, secondary glaucoma associated with non-acquired systemic condition; SCG-O, secondary glaucoma associated with ocular anomalies; SCG-A, secondary glaucoma associated with acquired conditions; GS, glaucoma suspect.

The onset of PCG was neonatal (≤1 month), infantile (>1 to 24 months), and late (>2 years) in 33 (37.5%), 38 (43.2%), and two (2.3%) patients, respectively. However, the onset was undetermined in 15 (17.1%) patients with PCG. Figure 2 outlines the distribution of the anomalies associated with SCG-O, SCG-S, and SCG-A. We could obtain angle data for 56 eyes with SCG-A, of which 44 (78.6%) and 12 (21.4%) eyes had open and closed angles, respectively.

Figure 2. Causes of secondary glaucoma subtypes that are associated with non-acquired systemic disease, non-acquired ocular anomalies, and acquired conditions.

SCG-C was mostly observed following a surgery for a congenital idiopathic cataract (n=19, 57.6%), followed by congenital cataract associated with ocular anomalies or systemic diseases (n=7, 21.2%), and acquired cataract (n=3, 9.1%). There were four patients (12.1%) that the type of cataract could not be specified.

While 157 glaucomatous eyes (29.5%) underwent an incisional surgery, 68 eyes (12.8%) underwent a cyclodestructive laser surgery. In contrast, 49 (9.2%) eyes required both incisional and cyclodestructive procedures at any time point during the follow-up period. Figure 3 and Table 3 presents the frequency of glaucoma intervention in each glaucoma type.

Figure 3. Type of glaucoma interventions in eyes with a glaucoma diagnosis.

PCG, primary congenital glaucoma; JOAG, juvenile open angle glaucoma; SCG-C, secondary glaucoma following cataract surgery; SCG-S, secondary glaucoma associated with non-acquired systemic condition; SCG-O, secondary glaucoma associated with ocular anomalies; SCG-A, secondary glaucoma associated with acquired conditions.

SCG-A had the highest proportion of favourable VA at the initial (57.5%) and latest (53.4%) visits. However, JOAG had the highest proportion of unfavourable VA at the initial (53.9%) and latest (73.3%) visits. We observed a higher proportion of unfavourable VA at the latest visit in the overall glaucoma cases (P=0.03), compared to that at the initial visit. A worsening of the VA was primarily observed in the SCG-O group. Despite an approach in the shift, it failed to attain a statistical significance (P=0.07). Moreover, the average IOP was 19.1±10.8 mmHg at the latest visit. All glaucoma types had significantly lower IOPs, compared to the baseline values (all p<0.001). Table 4 shows a comparison of the VA and IOP between the initial and latest visits for each glaucoma type.

The complete case analysis of 219 eyes showed that less favorable of initial visual acuity (p<0.001) and high last IOP (p<0.001) were significantly associated with poor visual outcome. In comparison to SCG-C, PCG (p=0.04), JOAG (p=0.01) and SCG-O (p=0.003) diagnoses were significantly associated with poor visual outcome. No significant risk of poor visual outcome was identified for the SCG-S and SCG-A groups when compared to the SCG-C group. (Table 5).

To elaborate more on the progression to unfavorable visual impairment, we further investigated the change of the VA group. Table 6 showed that most patients had no change in the VA group between the initial VA and the last VA. Most eyes with unfavorable last VA had already presented with unfavorable VA. The SCG-C tended to have an improvement of the VA. On the other hand, SCG-O had the highest proportion of worsening VA. None of JOAG had VA group change towards improvement.

Conclusions/discussion

Childhood glaucoma comprises a group of eye disorders that affect children from their birth with a juvenile onset. Our study had an average follow-up of 6 years. SCG-O (22.9%) was the most common subtype, followed by PCG (20.8%) and SCG-A (18.9%). The condition mostly affected boys, with the majority being bilateral cases, similar to previously published results¹⁶. Primary glaucoma, both PCG and JOAG, and SCG-O commonly require at least one type of glaucoma intervention. Following the treatment, we observed significant IOP improvements in all subtypes. Nonetheless, half of the cases demonstrated unfavourable VA at the final visit.

Existing literature has reported on a varied distribution of the subtypes^2,8–10,12. Most researchers have found a higher prevalence of secondary glaucoma, compared to primary glaucoma. However, reports from Canada⁶, Egypt⁹, Great Britain and the Republic of Ireland², and China⁷ have found that the majority of cases comprised PCG. The prevalence of secondary glaucoma depends on the prevalence of its aetiology (e.g. childhood cataract, hereditary systemic disease), which can differ among regions and ethnicities. Furthermore, this variation can be explained by the diagnostic criteria and study design. The diagnostic criteria of the studies conducted before 2013 were not based on the CGRN classification. In addition, hospital-based studies tend to have a higher proportion of complex cases, such as patients with syndromic and systemic involvement than those conducted in population-based settings. Table 7 summarises the distribution of childhood glaucoma according to the CGRN classification^{1,2,5–7,9–12}.

Leukocoria or corneal haze were the leading presenting symptom in PCG (46.9%) and SCG-O (77%) similar with previous studies^17–19. Moreover, most patients with JOAG were diagnosed without any symptoms. This could partially explain the most advanced stage at the time of diagnosis and the highest proportion of unfavourable VA outcomes in the aforementioned subtype. High IOP was the leading clue for glaucoma diagnosis. Furthermore, an enlarged corneal diameter was considered an important sign of PCG¹⁷.

We detected a family history of glaucoma in 6.4% of the 234 patients with an available family history. A study by Fung et al. reported on a family history of glaucoma in 17% patients with paediatric GS⁵. This high rate could be attributed to the tendency of having the eyes checked because of a family history of glaucoma. In our study, an exclusion of the GS cases would have reduced the rate of positive family history from 6.4% to only 5.7% (10 out of 174 patients). This value was half of that reported by Papadopoulos et al. (11%)². Despite the association of PCG and JOAG with certain mutations²⁰, our cohort revealed a positive family history in none of the PCG cases and in only one JOAG case. The true frequency of familial glaucoma, however, may be higher, as the data were available for only 55% of our patients. In addition, getting a family history without examining each family member tends to underestimate the actual occurrence of glaucoma in the family.

In line with the published literature, we found that surgical interventions were mostly required in the primary type of glaucoma, both PCG and JOAG. Moreover, medication was the mainstay of treatment for most secondary glaucoma cases². In addition, SCG-O cases reported a high rate of surgical intervention⁵. The pathology of the above-mentioned subtype is related to angle dysgenesis, which usually makes it difficult to control the disease.

Although PCG, JOAG and SCG-O had the high rate of surgical intervention, a high proportion of eyes that had no glaucoma interventions was observed in our study. The primary reason for not receiving surgical intervention was that the IOP could be controlled with medications. All patients with evidence of high IOP were offered surgical intervention (trabeculotomy and goniotomy) for PCG. The option of surgical intervention was discussed with the families of those who had previously been treated with medication. After seeing the well-controlled IOP, some parents preferred to continue with the medication. Unlike PCG, the surgical intervention was not necessarily offered to all SCG-O and JOAG patients. The decision to perform surgery in SCG-O was mainly based on the IOP and visual prognosis. Conservative treatment with medications was preferred If there was very limited vision potential such as nystagmus or visual acuity of light perception. For JOAG, the approach was quite similar to that for adult glaucoma. The majority of cases that did not receive glaucoma intervention underwent selective laser trabeculoplasty and were able to achieve target IOPs, though with medications.

Ramkrishanan et al. reported a significant improvement of VA, which was sustained for at least four years of follow-up²¹. This was in contrast to the marginally significant worsening of VA observed in our study. This disparity could be attributed to a greater proportion of PCG cases in the study conducted by Ramkrishanan et al. (Ramkrishanan et al. 73.3% vs our study 20.8%). The improvement of VA in their study was attributed to an improved corneal clarity following surgery.

We found that the SCG-A cases had the most favourable VA at the latest visit and the best initial VA. The majority of the cases included steroid-induced glaucoma, trauma and uveitis. In general, acquired conditions might be more controllable than the subtypes related to congenital ocular malformations, such as PCG and SCG-O. However, we found an overall worse VA, compared to that reported in previous publications^6,11,21. This discrepancy could be explained by the following aspects. First, we documented a high proportion of unfavourable VA during the initial visits. Khitri et al. reported on an association between poor vision at diagnosis and visual impairment (<20/200)²². Second, our cases were diagnosed at an extremely young age, particularly in the PCG (median age 0.5 years) and SCG-O (median age 0.3 years) groups. Studies on the PCG subtype reported on final VA <20/200 in children diagnosed before the age of three months regardless of their IOP levels^23,24. It was hypothesised that the earlier presentation reflected the poorer development of the angle. In other words, the disease was more severe. Nevertheless, the study design and definition of unfavourable VA differed among the studies.

Our study found that a less favorable initial VA and a high last IOP were significantly associated with a poor visual outcome. Most patients had no change in the VA group between the initial VA and the last VA. In addition, the diagnosis of PCG, JOAG, and SCG-O were significantly associated with poor visual outcome. The underlying ocular abnormalities tended to limit the visual potential in SCG-O, the anterior segment dysgenesis in particular. Our SCG-O cases with an unfavourable level at the latest visit either initially presented with an unfavourable VA or had an underlying anterior segment anomaly. It is worth mentioning that the JOAG in our study had a poor visual outcome despite having fewer issues regarding corneal problems or amblyopia than the other glaucoma types. All JOAG cases presented at a very advanced stage of disease with a median C:D ratio of 0.9. Our data demonstrated that the VA and glaucoma stage at presentation were the main factors determining the unfavourable VA, suggesting that early diagnosis and treatment are necessary to prevent this unpleasant result.

It should be noted that unfavourable VA could be a result from a combination of factors other than glaucoma such as underlying ocular pathology, uncorrected refractive error or amblyopia. As all patients were concomitantly seen by pediatric ophthalmologists, we believe that inadequate orthoptic exercise and inappropriate refractive correction would be less the case. However, due to the limitations of a retrospective study, it would be difficult to clearly delineate the cause of poor visual outcome in each patient.

Our study had the strength of being a large cohort study with a long follow-up duration. Our data also represents the majority of childhood glaucoma cases in Thailand. However, it had several limitations. First, there were some incomplete data because of the retrospective design. Moreover, information on some clinical examinations, such as VA and IOP could not always be obtained in children at every clinic visit. Second, the long follow-up period resulted in a shift in the IOP measurement methods from a handheld contact tonometer (Tono-Pen; Reichert, New York, USA) to a rebound tonometer (iCare TAO1i, Tiolat Oy, Helsinki, Finland) in extremely young or non-cooperative children. Third, there was inadequate information to clearly identify the cause of unfavourable VA outcomes. Future research should explore this underlying issue.

In conclusion, data from the referral centres in Thailand showed a higher prevalence of secondary glaucoma than primary glaucoma. Using the CGRN classification, secondary glaucoma associated with non-acquired ocular anomalies was found to be the most common subtype. All subtypes, including primary glaucoma, were sporadic. A majority of the cases had unfavourable visual outcomes. These real-world findings are fundamental data and provide a better understanding of childhood glaucoma.

Data availability