Efficacy of Penetrating Canaloplasty versus Trabeculectomy in Patients with Bilateral Primary Glaucoma: A Self-Control Study Open Access

Bleb-independent minimally invasive glaucoma surgery (MIGS) that attempts to restore the physiological trabeculocanalicular aqueous outflow pathway has been of great interest in the management of glaucoma [1‒7]. However, the majority of these MIGSs are recommended in eyes with an open angle. Previously, we developed a bleb-independent procedure of penetrating canaloplasty (PCP). It combines the procedures of tensioning suture-aided canaloplasty with a limbus fistula and peripheral iridectomy, allowing direct aqueous humor outflow from the anterior chamber to the Schlemm’s canal in eyes with either open or closed angle [8‒11]. Later, we modified this procedure in secondary angle-closure glaucoma with highly and extensively peripheral anterior synechia (PAS) (e.g., iridocorneal endothelial syndrome and Axenfeld-Riegar syndrome) by intentionally placing the limbal ostium and iridectomy at the location with the most extensive PAS boundary, creating a direct communication between posterior chamber and the Schlemm’s canal [12]. With the superficial scleral flap closed in a watertight manner and the absence of application of any antimetabolites, we propose PCP as a Schlemm’s canal-based bleb-independent glaucoma surgery. To date, we have confirmed the intraocular pressure (IOP)-lowering effect of PCP in eyes with primary angle-closure glaucoma (PACG), childhood glaucoma, angle recession glaucoma, steroid-induced glaucoma, as well as glaucoma secondary to iridocorneal endothelial syndrome [8‒12]. In the current study, we compared the efficacy and safety of PCP with the gold standard, mitomycin C-augmented trabeculectomy (TRAB) in patients with bilateral primary glaucoma.

This is a prospective non-randomized self-control interventional case series. Ethic committee approval was obtained from the Eye Hospital of Wenzhou Medical University (YX2018-016). The trial was registered at Chinese Clinical Trial Registry before recruitment (registration number: ChiCTR2100043112). The research adhered to the tenets of the Declaration of Helsinki. Written informed consent was obtained from participants prior to the study.

Patients aged 18 years or above with bilateral medically uncontrolled primary open angle glaucoma (POAG) or PACG were invited to participate. Medically uncontrolled glaucoma was defined as IOP >21 mm Hg with most tolerated antiglaucoma medications, or the patients were unwilling to use medications. Exclusive criteria included (1) previous surgeries in either eye other than laser periphery iridotomy or iridoplasty, (2) 360-degree circumferential cauterization not completed during PCP, (3) severe systemic diseases or mental illness, (4) pregnancy. Glaucoma was diagnosed according to the definitions of International Society for Geographical and Epidemiological Ophthalmology (ISGEO) [13]. POAG required 360-degree open angle, glaucomatous optic nerve changes with corresponding visual field defect, and no identifiable secondary cause for glaucoma. PACG was defined with ≥ 270° of the posterior trabecular meshwork not visible, with glaucomatous optic nerve changes and no secondary cause for glaucoma. TRAB was performed in the eye with more severe visual function loss (worse mean deviation), while PCP was performed in the fellow eye of the same patient.

Surgeries were performed by two experienced glaucoma surgeons (Y.L. and S.Z.) under topical anesthesia with the following standardized techniques.

Surgery began with a fornix-based conjunctiva flap and a 4 × 3 mm scleral flap of 1/3 to 1/2 scleral thickness at the superior quadrant. Two sponges soaked with 0.3–0.4 mg/mL mitomycin C were applied below the Tenon and scleral flap for 3 min according to the age and conjunctival status of the patients. A 1.5 × 0.5 mm limbal tissue underneath the scleral flap was excised and peripheral iridectomy was performed. The scleral flap was closed with 2–4 interrupted 10–0 nylon suture, allowing slow leaking of the aqueous humor with no anterior chamber shallowing. Then, the conjunctiva flap was watertightly closed.

Detailed procedures of PCP have been previously described [8‒12]. In brief, a fornix-based conjunctival flap was dissected in the superior quadrant. Beneath the 4 × 3 mm superficial scleral flap of 1/2 scleral thickness, a deep scleral flap (1.5 × 2 mm) was sculpted, and the Schlemm’s canal was carefully unroofed. A microcatheter (iTrack by Nova Eye, Hunt Town. SA 5067) was inserted into the Schlemm’s canal for 360-degree circumference. During withdrawn of the microcatheter, a single 10–0 polypropylene suture was guided into Schlemm’s canal and was knotted with tension to keep sustained dilation of the Schlemm’s canal. Meanwhile, a small amount of high molecular weight hyaluronic acid (Healon GV, Abbott Medical Optics Inc., Abbott Park, IL, USA) viscoelastic agent was also injected into Schlemm’s canal at two clock-hour intervals. Then, the deep flap was excised. A 1.5 × 0.5 mm limbal fistula anterior to the unroofed Schlemm’s canal was dissected with great caution. The anteriorly positioned limbal fistula not only avoids occlusion of the ostium by the peripheral iris or ciliary processes in eyes with narrow or closed angles but also provides additional protection to the tensioning suture in the SC during excision. Peripheral iridectomy was then performed to further prevent the occlusion of the fistula by the iris. Finally, the superficial scleral flap and the conjunctival flap were closed in a watertight fashion with 10-0 prolene sutures. Antimetabolites were not applied either during or after the surgery (Fig. 1).

Patients were followed up at day 1, week 1, months 1, 3, 6, 12, and 24. IOP, antiglaucoma medications, intra- and postoperative complications, and supplementary interventions after the surgery were recorded. Filtering bleb was assessed by slit-lamp biomicroscope and ultrasound biomicroscopy (UBM). The filtering blebs were divided into the L-type (low-reflective), H-type (highly reflective), E-type (encapsulated), and F-type (flattened) according to the UBM images [14, 15]. L- and H-type blebs were defined as functional, whereas E- and F-type blebs were defined as nonfunctional. Complete (without medication) and qualified success (with or without medication) were defined as an IOP ≤21 mm Hg and ≥20% IOP reduction, IOP ≥5 mm Hg, no vision loss attributable to glaucoma, and no need for further glaucoma surgery [16, 17].

Statistical analyses were performed by SPSS 24.0 software (SPSS Inc., Chicago, IL, USA). IOP and number of glaucoma medications between baseline and each follow-up after the surgery were compared using paired repeated measured ANOVA. Paired chi-square test or Fisher’s exact test was performed to compare the medications, success rate, and incidence of complications between two surgical procedures. A p < 0.05 was considered statistically significant.

We finally enrolled 27 patients with bilateral uncontrolled primary glaucoma (18 POAG and 9 PACG). The flowchart of this study was supplemented in Figure S1 (for all online suppl. material, see https://doi.org/10.1159/000546133). They comprised 23 males and 4 females with a mean age of 54.1 ± 10.7 years (range, 27–69 years). Among these patients, PCP was performed in the right eye in 15/27 (55.6%) patients. Demographic and clinical characteristics of these patients are shown in Table 1. Preoperative IOP was 32.5 ± 8.87 mm Hg for TRAB group and 30.0 ± 9.61 mm Hg for PCP group (p = 0.973). Eyes in TRAB group used less medications (2.26 ± 1.43) compared with PCP group at baseline (2.70 ± 1.10, p = 0.023). Preoperative best corrected visual acuity (BCVA) was better in PCP group (0.17 ± 0.24) than that in TRAB group (0.84 ± 1.14, p = 0.006), while visual field mean deviation was similar between groups (−25.4 ± 9.45 dB versus −21.0 ± 8.95 dB, p = 0.094). All (100%) patients completed the 6-month follow-up and 25 (92.6%) finished the 24-month follow-up (1 patient died due to traffic accident at 8 months, 1 patient lost follow-up after 6 months). The average follow-up was 26.22 months (range, 6–36 month).

Both surgical procedures significantly reduced the IOP during follow-up (all p < 0.001). The mean IOP decreased to 14.7 ± 3.54 mm Hg on 0.19 ± 0.68 medications in TRAB group and 13.8 ± 3.09 mm Hg on 0.15 ± 0.60 medications in PCP group at 6 months. At 12 months after the surgery, the IOP was 14.6 ± 4.41 mm Hg on 0.20 ± 0.58 medications in TRAB group and 14.8 ± 4.63 mm Hg on 0.12 ± 0.44 medications in PCP group. The mean IOP was 15.5 ± 5.02 mm Hg on 0.12 ± 0.33 medications in TRAB group and 15.5 ± 4.36 mm Hg on 0.40 ± 0.82 medications in PCP group at 24 months. IOP at the last follow-up was 15.4 ± 4.94 mm Hg on 0.16 ± 0.47 medications in TRAB group and 16.0 ± 5.38 mm Hg on 0.35 ± 0.80 medications in PCP group (IOP: p = 0.6745, medications: p = 0.1344). No difference in IOP and medications were detected at each follow-up time (all p > 0.05) between two groups (Table 2; Fig. 2). In both TRAB and PCP group, 21 among 25 eyes (84.0%) were classified as complete success at 12 months (Fisher’s exact test, p > 0.9999). Among these eyes, 12 (48%) eyes in the TRAB group achieved an IOP <15 mm Hg compared with 14 (56%) eyes in the PCP group at 1-year follow-up (p = 0.561). Twenty-four (96.0%) and 22 (88.0%) eyes met the criteria of qualified success in the TRAB and PCP group after 12 months, respectively (Fisher’s exact test, p = 0.609). At 24 months, the qualified success rate was 80.0% in TRAB group and 88.0% in PCP group in total (p = 0.702). No difference in surgical success was observed between different glaucoma subtypes (all p > 0.05) (Table 3).

Early postoperative hypotony-associated choroidal detachment and anterior chamber shallowing occurred in 4 eyes (14.8%) after TRAB. The other common complication was wound leakage (3/27, 11.1%), with two cases alleviated after bandage compression and one with surgical revision. Bleb management was administered in 17 eyes (63.0%) in TRAB group. Among them, 40.7% (11/27) eyes received bleb needling with antimetabolites injection. Laser suture lysis was performed in 7 eyes (25.9%). Bleb massage was advised in 8 (29.6%) eyes. The most frequently observed postoperative complications in PCP group were microhyphema (6/27, 22.2%) and transient IOP elevation of >25 mm Hg (22.2%, 6/27). Hypotony-associated anterior chamber shallowing occurred in 2 eyes (7.41%) after PCP, which spontaneously resolved within 1 week after the surgery. Virus keratitis was diagnosed after PCP in one eye (3.7%). No other severe complications were observed after PCP. Foreign body sensation and discomfort of ocular surface were reported by 48.1% eyes in TRAB group versus 14.8% in PCP group (Fisher’s exact test, p = 0.018).

Two (7.4%) of the eyes in PCP group and 22 (81.5%) eyes in TRAB group bore visible filtering bleb under slit lamp at their last visits. Regarding the frequency distribution of UBM-based bleb types, 25 (92.6%) eyes in the PCP group were classified as F-type. In contrast, 20 (74.1%), 2 (7.4%), and 5 (18.5%) eyes in TRAB were defined as L-, H-, and F-type bleb, respectively (chi-squared test, p < 0.001). Figure 3 showed representative UBM images of blebs for eyes after TRAB and PCP that showed good IOP control.

Since its first introduction in 1968 by Cairns, TRAB remains the most common glaucoma surgery and is regarded as the gold standard in the surgical management of glaucoma. Although it is now consistently perceived to function by subconjunctival aqueous humor drainage, TRAB was first described to enhance outflow through the excised trabecular meshwork into the Schlemm’s canal [18]. Advance of technology provides opportunities for the original vision of TRAB to be realized. PCP restores physiological outflow by directing aqueous humor flows from the anterior or posterior chamber into the tensioning suture-dilated Schlemm’s canal through a fistula at the limbus [8‒11]. In the present prospective self-control study, we observed comparable IOP-lowering effect of PCP with that of TRAB in eyes with both POAG and PACG over at least 1 year. This bleb-independent and angle status-independent procedure greatly avoids bleb-related complications and postoperative interventions, as well as less self-reported symptoms of foreign body sensation that are common after TRAB.

Schlemm’s canal-based MIGS are gaining increasing recognition and acceptance in the management of glaucoma [19, 20]. Most studies reported lower efficacy in IOP reduction of bled-independent procedures than subconjunctival filtering surgeries [21‒23]. A recent systematic review study suggested that TRAB is more effective in reducing IOP than non-penetrating surgeries at both 6 and 12 months after surgery (−2.15 mm Hg and −2.22 mm Hg, respectively) [23]. Matlach and colleagues reported a complete success of 67.7% and 39.1% at 2 years after TRAB (11.5 ± 3.4 mm Hg) and canaloplasty (14.4 ± 4.2 mm Hg), respectively [16]. TRAB led to greater IOP reduction (56.05 ± 17.72% vs. 42.04 ± 15.56%) and higher surgical success (86% vs. 77%) than gonioscopy-assisted transluminal trabeculotomy at 18 months in POAG eyes [24]. Similarly, XEN GEL iStent implantation achieved significantly higher IOP reduction (57.9% vs. 37.1%) and success rates (97.4% vs. 89.7%) than gonioscopy-assisted transluminal trabeculotomy (GATT) [25]. Differing from these studies, we observed similar IOP-lowering efficacy of PCP with TRAB in patients with primary glaucoma in the present study. Reasons may be as following. First, in both POAG and PACG, the main resistance of aqueous humor outflow exists in the dysfunctional or closed anterior chamber angle. Penetrating Schlemm’s canal surgeries that create direct communication between the anterior chamber and Schlemm’s canal may achieve additional IOP decrease compared with non-penetrating surgeries. To support this, laser goniopuncture was able to further decrease IOP after canaloplasty (from 20.6 ± 4.2 to 14.2 ± 2.2 mm Hg) [26]. Baumgarten and colleagues reported a complete and qualified success of 25% and 70%, respectively, for microinvasive 360° trabeculotomy after unsuccessful canaloplasty [27]. Consistently, we also observed more superior IOP-lowering effect of PCP compared with canaloplasty in POAG eyes (46.4% vs. 33.2%) in a randomized comparative study (unpublished data). Second, the combination of tensioning suture aided Schlemm’s canal dilation, limbus fistula and peripheral iridectomy in PCP permitting a consistent dilation of the Schlemm’s canal, further decrease in outflow resistance at trabecular meshwork and avoiding herniation of the peripheral iris into the limbal fistula [28, 29]. Since the main steps of PCP are all common procedures in clinics, surgeons with experience of TRAB and Schlemm’s canal surgeries can master the technique of PCP with a relatively short learning curve. Other groups reported similar results with us regarding the effect of PCP in treating primary and secondary glaucoma [30‒32].

In the present study, PCP achieved a mean IOP of 14.8 ± 4.63 mm Hg at 12 months. A total of 66.7% eyes among those with complete success after PCP (14/21) showed postoperative IOP <15 mm Hg. This is consistent with our previous study on the distribution of postoperative IOP after successful canaloplasty and PCP, which reported a mean postoperative IOP of 13.9 ± 3.3 mm Hg, and the percentage of IOP <12, 15, and 18 mm Hg was 33.9%, 67%, and 90.7%, respectively [33]. The IOP-lowering effect of Schlemm’s canal surgeries is highly dependent on the resistance of the distal outflow system and the pressure in the episcleral vasculature [34, 35]. Our previous study on the IOP distribution among healthy adults 50 years and older reported a mean IOP of 13.5 ± 3.0 mm Hg. The percentage of IOP <12, 15, and 18 mm Hg was 34.8%, 70.3%, and 91.5%, respectively [36]. Similar IOP distribution between PCP and healthy eyes may suggest the restoration of physical outflow pathway after surgery in these eyes, which is also related to a relatively more predictable postoperative IOP. In contrast, although TRAB is usually considered to be favorable regarding IOP reduction, postoperative IOP is highly dependent on a functioning filtering bleb, which is difficult to predict [37]. The ability of achieving stable physiological IOP level after PCP is essential in ceasing disease progression in patients with early and moderate glaucoma. In addition, although not statistically significant, the PCP group seems to need more medications at the last follow-up in our present study. As discussed above, being an internal filtration surgery, the postoperative IOP of PCP is highly dependent on the pressure of episcleral vein. Even complete success is achieved, the patients and ophthalmologists may prefer to use additional medications to achieve a further lower target IOP. Prospective studies with larger sample size and longer follow-up are needed to draw a much more solid conclusion.

We propose PCP as a bleb-independent procedure which achieves internal aqueous humor outflow from the intraocular chamber to Schlemm’s canal in eyes with either open or closed angles. With the watertight closed scleral flap and the absence of anti-metabolites, we aim to maximally avoid the subconjunctival filtration in PCP. In the present study, the morphology of the blebs was assessed by slit lamp and UBM. A total of 92.6% of the eyes in PCP group were classified as F-type based on the UBM imaging, suggesting a nonfunctional feature of these blebs. However, two eyes consistently showed an L-type bleb after the PCP. The exclusion of potential drainage through subconjunctival space in PCP is still challenging. The exact mechanism for the IOP-lowering effect of PCP can still only be proposed at present and a better elucidation will depend on aqueous humor angiography.

Similar with other Schlemm’s canal surgeries, PCP showed less bleb-related complications and less requirement of postoperative interventions than TRAB [20, 38‒40]. The prevalence of hypotony and choroidal detachment after TRAB was 8.0%–48.1% depending on different studies [16, 41‒44]. Reiter et al. [45] reported that 87.8% of patients need 5-FU injection after TRAB (half needed >7 injections), and others reported a postoperative bleb intervention rate of 63.9%–78.2% [38, 46]. With watertight closure of the scleral flap, lower incidence of hypotony or associated complications was observed in PCP group (7.4%) compared with TRAB (14.8%). Meanwhile, the characteristic of bleb independence of PCP also lead to fewer postoperative suture lysis (0 vs. 25.9%), bleb needling and 5-FU injection (0 vs. 40.7%), which may subsequently lead to less clinical visits. With these advantages, it is not surprising that the proportion of patients with ocular discomfort in PCP group was less than that in TRAB group.

Transient hyphema and IOP spikes are the most common complications associated with PCP. Transient IOP spike has been widely reported in various Schlemm’s canal surgeries, like canaloplasty (3% >30 mm Hg to 30% >25 mm Hg) [26, 47, 48] and iStent implantation (10.1%–21%) [1, 3, 49], and various glaucoma subtypes (childhood glaucoma, POAG, PACG, traumatic angle recession glaucoma, and iridocorneal endothelial syndrome) [8‒12]. Underlying mechanism of this phenomenon has not been clearly elucidated. In addition to early residual of viscoelastic agent, blood, exudative materials in Schlemm’s canal, re-dredge of the collapsed distal outflow channels secondary to long-term IOP elevation may play a key role in this transient IOP elevation. This postoperative IOP spike in Schlemm’s surgeries including PCP not only brings insight into the pathophysiology of glaucoma but also brings new challenges for the clinical care and prognosis of the patients, which deserves more attention in the future.

This study still has some limitations. First, the sample size is relatively small, especially patients with PACG. Lens extraction with or without goniolysis was recommended by various guidelines for the management of PACG [50]. So, we only enrolled PACG patients with extensive peripheral synechia (>270°) and who may not benefit from a cataract surgery (without obvious cataract or with severe optic neuropathy and poor visual function), which greatly limited the sample size of PACG. And the sample power could also be small due to the small sample size which could compromise the outcome in this study. Therefore, we could not tell whether different efficacy of these surgical procedures exist between different glaucoma subtypes from present data. And further outcome of this study should be observed. Secondary, present study only reported the results up to 1 year after surgery. Long-term follow-up will help elucidate the efficacy of PCP in comparison to TRAB. Third, present study is a self-control un-randomized study. Although most of the baseline parameters were comparable between two groups, the possibility of selection bias still exists. A randomized case-control study should be performed for a more solid conclusion. Finally, we only enrolled patients with bilaterally high pressures. Efficacy of PCP in eyes with normal tension glaucoma was not investigated. Previous studies have confirmed the feasibility of iStent and hydrus in treating normal tension glaucoma [51, 52]. Given the similar IOP-lowering mechanism of these SC-based surgeries, PCP may also bring benefit in eyes with normal or low tension glaucoma.

The present study is the first report of a prospective, self-control comparison of PCP and TRAB in fellow eyes of the same patient with a 12-month follow-up visit. The result demonstrates that PCP has similar IOP reduction and surgical success compared to TRAB, but with lower incidence of postoperative complications, additional interventions, and better ocular comfort.

Ethic committee approval was obtained from the Eye Hospital of Wenzhou Medical University (YX2018-016). The trial was registered at Chinese Clinical Trial Registry before recruitment (registration number: ChiCTR2100043112). The research adhered to the tenets of the Declaration of Helsinki. Written informed consent was obtained from participants prior to the study.

The authors have no conflicts of interest to declare.

This study was funded by National Key R&D Program of China (2020YFC2008200), Key R&D Program of Zhejiang (2022C03112), and Key Innovation and Guidance Program of the Eye Hospital, School of Ophthalmology and Optometry, Wenzhou Medical University (YNZD2201903).

Study design and ethical approval: Wenqing Ye and Haishuang Lin. Data collection: Xiaowei Xu, Jinxin Li, Shuqing Zhu, and Yanqian Xie. Data management and interpretation: Wenqing Ye, Xiaowei Xu, Jinxin Li, and Shuqing Zhu. Statistical analysis: Wenqing Ye and Haishuang Lin. Manuscript drafting: Wenqing Ye, Xiaowei Xu, and Shaodan Zhang. Manuscript reviewing and approval and allocation of resources: Shaodan Zhang and Yuanbo Liang.

Wenqing Ye and Xiaowei Xu contributed equally to this work.

The data that support the findings of this study are not publicly available due to their containing information that could compromise the privacy of research participants but are available from the corresponding author (S.Z.) upon reasonable request.