Combined Trabeculotomy-Non-Penetrating Deep Sclerectomy for Glaucoma in Sturge-Weber Syndrome

Sturge-Weber syndrome (SWS) is a rare, congenital, multisystem disorder affecting approximately 1 in 50,000 individuals. It is characterized by facial port-wine stain (PWS), leptomeningeal angiomas, and glaucoma [1]. Clinical manifestations also include cognitive delays, seizures, and choroidal hemangioma. Estimates suggest that 30–71% of patients have glaucoma, with 60% developing it during infancy and 40% having juvenile- or adulthood-onset glaucoma [2‒8].

Previously, ophthalmologists believed that abnormal anterior chamber angles were the cause of SWS early-onset glaucoma, while increased episcleral venous pressure (EVP) was responsible for juvenile- or adulthood-onset glaucoma [9‒12]. Our previous study found that trabeculotomy had good intermediate-term surgical outcomes for early-onset glaucoma [13]. However, we later discovered that the outcome of trabeculotomy for patients with more severe episcleral vascular malformation was not ideal [14]. This strongly suggests that malformed episcleral vasculatures, which drain aqueous humor, may also contribute to SWS early-onset glaucoma. Researchers have validated the increased scleral venous pressure in the affected eye with the help of specific equipment [11, 12]. Therefore, surgical interventions that address both the elevated EVP and angle deformity effectively may lead to a better prognosis in SWS.

Due to the presence of choroidal hemangioma, a sudden drop in intraocular pressure (IOP) during filtering surgery increases the risk of choroidal detachment or choroidal effusion in SWS [15‒23]. In 1964, Krasnov reported the first non-penetrating filtering surgery, known as sinusotomy [24]. Since then, the surgical process has been continuously improved, and non-penetrating deep sclerectomy (NPDS) has become one of the most popular non-penetrating filtering surgeries. NPDS involves the removal of the juxtacanalicular trabeculum and Schlemm’s canal endothelium, as well as the creation of an intrascleral space and a trabeculo-Descemet’s membrane (TDM) [25]. The two main hypothetical mechanisms of aqueous resorption are subconjunctival filtering bleb and suprachoroidal filtration, both of which are independent of EVP [26]. Compared to trabeculectomy, NPDS results in similar IOP reduction but with fewer complications in the early postoperative period, as the procedure does not penetrate into the anterior chamber and the TDM allows a slow decrease of IOP [27]. Therefore, we combined trabeculotomy and NPDS to pursue a higher success rate and a lower complication rate in SWS. This study assesses the outcome of combined trabeculotomy-non-penetrating deep sclerectomy (CTNS) in SWS secondary glaucoma patients.

This retrospective study reviewed 23 eyes of 22 SWS secondary glaucoma patients who underwent CTNS as initial treatment at the Department of Ophthalmology, Shanghai Ninth People’s Hospital, from April 2019 to August 2020. This study was conducted in accordance with the Declaration of Helsinki and was ethically approved by the Institutional Review Board of the Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, with the approval number being [SH9H-2021-T253-1]. Written informed consent was waived due to the retrospective nature of the study. The diagnosis, surgery, follow-up, and necessary treatment were all provided by the same ophthalmologist (W.G.).

All patients included in this study had either unilateral or bilateral facial PWS and glaucoma. The diagnosis of port-wine stain was made by the Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital. For infants, only those with multiple episcleral vascular abnormal network underwent CTNS, as per the previously stated criteria for multiple episcleral vascular abnormal network [14].

For children, the diagnosis of glaucoma required the presence of at least two of the following criteria [1, 28]: (1) IOP >21 mm Hg or obvious asymmetry between the 2 eyes (=6 mm Hg); (2) a cup-to-disc ratio (C/D) > 0.5 or obvious asymmetry C/D between the 2 eyes (=0.2); (3) cornea findings: diameter enlargement (diameter >11 mm in newborns, >12 mm for children <1 year old, or >13 mm for any age), obvious asymmetry cornea diameter between the 2 eyes, corneal edema, or Haab striae; (4) typical visual field loss and retinal nerve fiber layer defects; (5) progressive myopia or myopia shift with increased ocular dimensions that outpace. For adults, the diagnosis of glaucoma required the presence of at least two of the following criteria: (1) IOP >21 mm Hg; (2) C/D > 0.5 or obvious asymmetry C/D between the 2 eyes (=0.2); (3) typical visual field loss and retinal nerve fiber layer defects.

SWS early-onset glaucoma is defined as meeting the criteria for SWS secondary glaucoma, plus any of the following [1]: (1) age at diagnosis is =3 years; (2) corneal diameter enlargement, or the difference in diameter from the unaffected side is =0.5 mm. SWS late-onset glaucoma is defined as meeting the diagnosis of SWS secondary glaucoma but not meeting the diagnosis of early-onset glaucoma.

(1) A fornix-based conjunctival flap (Fig. 1a) was created. (2) A 5 × 5 mm limbus-based superficial scleral flap was cut 2 mm anteriorly into the clear cornea, including one-third of the total scleral thickness (Fig. 1b). (3) A sponge soaked in 25 mg/mL solution of 5-fluorouracil was placed under the superficial scleral flap and conjunctival flap for 3 min (Fig. 1c, d). (4) The eye was washed with 20 mL of balanced salt solution. (5) A rectangular deep scleral flap (4 × 4 mm) smaller than the superficial one was created (Fig. 1e). The remaining TDM should be as thin as possible. On reaching the anterior part of the dissection, the outer wall of Schlemm’s canal was left uncut. (6) The incision was deepened at the gray-white junction on both sides of the deep scleral flap until the outer wall of the Schlemm’s canal was cut (Fig. 1f). (7) The trabeculotomy probe was introduced into the temporal canal from the temporal radial incision and rotated into the anterior chamber (Fig. 1g). Similar trabeculotomy was performed from the nasal incision. In total, about 120° of the trabecular meshwork was ruptured. (8) The deep scleral flap was extended anteriorly until the Schlemm’s canal was encountered and unroofed. The deep scleral flap together with the outer wall of Schlemm’s canal were removed at this stage (Fig. 1h). (9) The Schlemm’s canal endothelium and the juxtacanalicular trabeculum were peeled off softly (Fig. 1i). At this procedure stage, there should be an evident percolation of aqueous humor through the remaining trabeculum. (10) The superficial scleral flap was repositioned and sutured. (11) Viscoelasticity was injected under the superficial scleral flap (Fig. 1j). (12) After suturing the conjunctival flap, pilocarpine was applied topically directly to the eye.

Data were retrieved from clinical records. The parameters recorded included IOP, C/D, anti-glaucoma medications (prior to and after surgery), history of anti-glaucoma surgery, and epileptic seizures. Complications throughout the follow-up period were recorded.

Success and failure were defined in accordance to the 2008 World Glaucoma Association consensus [29]. Complete success was defined as IOP =21 mm Hg without anti-glaucoma medications. Qualified success was defined as IOP =21 mm Hg with anti-glaucoma medication. Overall success included complete success and qualified success. Failure was defined as: (1) IOP >21 mm Hg or <5 mm Hg despite application of 3 or more anti-glaucoma medications on 2 consecutive follow-up visits or at the last follow-up; (2) performance of additional glaucoma (IOP-lowering) surgery; (3) with vision-threatening complications.

• 1.

  Follow-up was less than 1 year.

• 2.

  Uncompletion of CTNS.

Statistical analysis was performed using GraphPad Prism software, version 8.0. Normality was assessed with the Shapiro-Wilk test, and quantitative variables exhibiting a normal distribution were reported as the mean and standard deviation. For non-normal variables, the median and interquartile range (IQR) were presented. An unpaired t test was used to compare the preoperative IOP between glaucomatous eyes and fellow eyes, while the Mann-Whitney test was used to compare the corneal diameter and central corneal thickness (C/D) between the two groups. Dunnett’s multiple comparisons test was applied to the IOPs at each follow-up. Results were considered significant with a p < 0.05.

Overall, a total of 22 eyes from 21 patients underwent CTNS, with a minimum of 1 year of follow-up, where 1 patient (1 eye) was excluded for not completing CTNS. Of those patients, 13 were male and 8 were female; 1 required surgery in both eyes due to bilateral glaucoma and bilateral facial PWS. Altogether, 21 eyes were of early-onset type, 20 (91.0%) eyes had thickened choroid or choroidal hemangioma, 3 (14.3%) patients were detected with clinical seizures, and 7 (31.8%) eyes had corneal edema. The baseline demographic characteristics are summarized in Table 1. The median age of the patients at the time of surgery was 4.6 (IQR: 2.2, 8.0) years, with a range of 0.2–30.3 years. The average preoperative IOP in the glaucomatous eyes was 25.4 ± 5.6 mm Hg and 13.7 ± 5.0 mm Hg in the contralateral eyes. The median C/D in the glaucomatous and fellow eyes were 0.80 (IQR: 0.68, 0.86) and 0.30 (IQR: 0.26, 0.40), respectively. The median corneal diameter of the glaucomatous and fellow eyes were 13.00 (IQR: 12.43, 13.43) mm and 11.75 (IQR: 11.50, 12.00) mm, respectively.

For SWS early-onset patients, Kaplan-Meier survival analysis shows the overall success rates at the 1st and 2nd years were 95.2% and 84.9%, respectively, while the complete success rates were 42.9% and 36.7% (Fig. 2). At the final follow-up (22.3 ± 4.0 months, range: 11.2~31.2), overall success was achieved in 18 (18/21, 85.7%) eyes and complete success in 11 (11/21, 52.4%) eyes. The adult-onset glaucoma eye achieved complete success at the last follow-up (12.4 months).

Low to moderately elevated blebs were seen in 17 (17/22, 77.3%) eyes. The IOP significantly decreased from 25.4 ± 5.6 at baseline to 18.2 ± 5.1 at the last follow-up (p < 0.0001), with significant decreases evident at each follow-up: 1st week (15.6 ± 5.5, p < 0.0001), 1st month (17.1 ± 5.8, p = 0.0001), 6th month (18.2 ± 7.9, p = 0.0004), 1 year (20.1 ± 5.8, p = 0.0179), 1.5 year (19.1 ± 4.8, p = 0.0034), and 2 years (18.9 ± 4.1, p = 0.0031) (Fig. 3 and Table 2). The number of anti-glaucoma medicines in follow-up is shown in Table 3. The number of patients with anti-glaucoma medicines declined from 14 to 10 at the last follow-up. The median (IQR) of the number of medications was 1.5 (0, 3) at baseline and 0 (0, 2.25) at the last follow-up.

No participant received additional interventions, such as bleb needling or second anti-glaucoma surgeries, during the follow-up period. During the surgery, trabecular meshwork tear and iris prolapse occurred in 1 patient (1/23, 4.3%), who was subsequently excluded from the analysis in the article. Postoperative complications included transient hyphema (11/22, 50.0%) and transient I degree shallow anterior chamber (1/22, 4.5%), which resolved without intervention by the first week. One patient with bilateral CTNS had a unilateral retinal detachment (1/22, 4.5%) at the first-week follow-up, which was confirmed by B-scan to have healed during the follow-up. No other serious complications were detected during the follow-up.

We conducted a Cox regression analysis on early-onset participants to investigate risk factors for postoperative IOP escalating beyond 21 mm Hg (the time at which the success rate is reduced). PWS (unilateral/bilateral), age, corneal edema (yes/no), corneal diameter, C/D, hyphema (yes/no), choroid thickening (yes/no), gender (male/female), preoperative IOP, preoperative medication (yes/no) were the initial variables included in the model, and stepwise regression based on AIC value was used for variable screening. The results revealed that males were less likely to experience postoperative IOP elevation, while high preoperative IOP and preoperative medication were risk factors for postoperative IOP elevation (p < 0.05), and other variables were not significantly associated with postoperative IOP elevation (Table 4).

Glaucoma is a leading cause of irreversible blindness, severely affecting the quality of life of those affected due to progressive visual field defects and the need for lifelong treatment. For patients with SWS, the situation is even worse, with many SWS secondary glaucoma patients developing glaucoma within the first year of life [2, 30]. This can lead to an increased financial burden on families. In addition, topical medications often fail to achieve the desired IOP, particularly in early-onset cases [31], and complications such as choroidal/retinal detachment and suprachoroidal hemorrhage are more common. Ophthalmologists are dedicated to improving the lives of these patients.

It was previously thought that angle dysplasia was the primary cause of early-onset glaucoma in Sturge-Weber syndrome (SWS); thus, the treatment often employed was trabeculotomy, similar to what is used for primary congenital glaucoma (PCG). Although there were some studies showing changes in the trabecula of SWS [32], some of our findings suggest that the angle structure of SWS early-onset glaucoma is different from that of PCG: (1) Gonioscopy reveals a lack of mesodermal tissue in SWS; (2) the IOP of SWS early-onset glaucoma is often not very high; Haab’s striae are not as common; (3) after the removal of Schlemm’s canal’s inner wall during CTNS, aqueous humor is able to exudate through the TDM. This implies that the trabeculae of SWS may not be the major site of resistance to the outflow of aqueous humor in SWS. Our prior study demonstrated that SWS early-onset glaucoma patients with pronounced scleral vascular malformations have a relatively poor response to trabeculotomy, indicating that vascular elements may be implicated in the emergence of SWS early-onset glaucoma patients [14]. In addition, we identified a GNAQ R183Q mutation in the scleral vessels of SWS, which is believed to be a major cause of vascular malformations in SWS [33]. Since Schlemm’s canal develops from scleral veins [34], morphological and functional abnormalities may also be present in the Schlemm’s canal in SWS. We suppose that the aqueous outflow resistance of SWS early-onset glaucoma patients is mainly located in Schlemm’s canal. With age, the scleral vascular malformation becomes increasingly severe, and the EVP gradually increases. The distal resistance thus becomes the primary pathogenic factor. Some early-onset patients with a serious episcleral vascular malformation may already have an increasing distal resistance in the early stage. The specific action mechanism of trabeculotomy in SWS may differ from that of PCG. Trabeculotomy mainly resolve the obstruction in trabecular meshwork in PCG, while it may aim at the inner wall of the Schlemm’s canal in SWS. Therefore, trabeculotomy is insufficient for patients with severe episcleral vascular malformations present at birth.

In this study, we first described a novel surgical method – CTNS – for SWS adulthood-onset glaucoma and early-onset glaucoma patients with severe episcleral vascular malformation. CTNS combines trabeculotomy and NPDS to address the resistance anterior to the inner wall of Schlemm’s canal and posterior to the outer wall of the canal, respectively. The aqueous humor can either enter the Schlemm’s canal directly from the anterior chamber through the incision of trabeculotomy or enter the scleral concave pool through TDM, then drain into the suprachoroidal space, scleral connective tissue, and subconjunctiva.

Finally, the overall success rates at the 1st and 2nd year follow-up points were 95.2% and 84.9%, respectively, while the complete success rates were 42.9% and 36.7%. Of note, the IOP of 3 qualified success patients fell below 21 mm Hg without medicine, after a short-term anti-glaucoma medication therapy. IOP was significantly decreased at each subsequent follow-up. Considering the poor prognosis of adult and child patients with severe episcleral vasculature malformation enrolled in this study, the efficiency of CTNS in SWS is encouraging.

Studies in both PCG and POAG have demonstrated that males are at a greater risk for disease progression [35, 36]. In this study, males were found to be less likely to experience an elevation in IOP postoperatively. This may suggest a different pathogenesis of SWS secondary glaucoma. Other gender-related factors, such as hormones and outdoor activities, should not be overlooked, as they may be prime research areas for the future [37, 38].

Due to the presence of choroidal hemangioma, there is an increased risk of exudation during filtration surgery due to the sudden drop in IOP. To the best of our knowledge, choroidal detachment rate (4.5% vs. 10~57.1%) in our case series is fairly low (Table 5) [15, 17‒23]. Though most of the patients (90.9%) had choroidal hemangioma or choroidal thickening, only a 4-year-old male child developed retinal detachment at 1st week after CTNS. We believe this low choroidal detachment rate is likely due to the slight variations of IOP during and after CTNS, as CTNS did not penetrate into the anterior chamber and TDM provides moderate resistance to aqueous humor drainage.

CTNS allows for aqueous humor to enter the subconjunctival space through a scleral incision, thereby creating subconjunctival drainage. Given the rapid wound healing in young patients, we used 25 mg/mL of 5-fluorouracil sponge placed under the conjunctival sac and scleral flap for 3 min after the superficial scleral flap of CTNS was created for anti-scarring treatment. Our findings revealed that in 77.3% (17/22) of eyes, low to moderately elevated blebs were present at the last follow-up. This proportion is similar to that of combined trabeculotomy-trabeculectomy in PCG [39, 40]. It is possible that this proportion is underestimated in the current study, as children unable to cooperate were categorized as not observed.

The limitations of CTNS were also present, with NPDS and trabeculotomy having a long learning curve and the combination of the two procedures potentially resulting in trabecular meshwork tear and iris prolapse. To reduce the risk, we performed trabeculotomy before unroofing the Schlemm’s canal, and only 1 patient had iris prolapse. Our current research is a retrospective non-comparative case series, and a prospective randomized controlled study is needed to demonstrate the efficacy and safety of CTNS. Besides, our study is limited by its short follow-up, with a previous study reviewing the outcome of combined trabeculotomy-trabeculectomy over a period of 23 years, finding that more than half (15/26, 57.7%) of SWS secondary glaucoma requires secondary surgery in a mean duration of 23.13 ± 24.41 months [41]. The long-term efficiency of CTNS in young SWS patients with serious episcleral vascular malformation deserves further exploration. We will keep a close and constant observation of these patients and believe that this study still provides useful experience in managing SWS secondary glaucoma.

CTNS significantly reduces IOP in SWS secondary glaucoma patients who have serious episcleral vascular malformation. CTNS in SWS secondary glaucoma patients is safe and effective for short and medium periods. A randomized controlled study comparing the long-term prognosis of SWS early-onset and late-onset glaucoma underwent CTNS is worth conducting.

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, approval number [SH9H-2021-T253-1]. Informed consent is waived due to the retrospective nature of the study.

The authors declare no competing interests.

This work was supported by the National Natural Science Foundation of China (No. 81970796, No. 82171046, No. 82101114), Clinical Research Program of Shanghai Municipal Health Commission (No. 201940330), Clinical Research Program of 9th People’s Hospital affiliated to Shanghai Jiao Tong University School of Medicine (No. JYLJ201904), Clinical Research Plan of SHDC (SHDC2020CR6029), Cross-Disciplinary Research Fund of Shanghai Ninth People’s Hospital, Shanghai JiaoTong University School of Medicine (YG2019QNA18), and the Research Grant of the Shanghai Science and Technology Committee (No. 20DZ2270800). The authors have no financial disclosures to declare in relation to this study.

L.H., Y.W., and W.G. contributed to study design, data analysis and interpretation, and drafted the manuscript. L.X., Y.L., Y.Y., N.W., M.G., and C.S. contributed to data collection and data analysis. W.G. conceived the study and reviewed and revised the manuscript. All authors read and approved the final manuscript.

Data are not publicly available due to ethical reasons. Further inquiries can be directed to the corresponding author.