FormalPara Key Summary Points

Why carry out this study?

BEST1-associated retinopathy, especially for autosomal recessive bestrophinopathy, is often characterized as hyperopia, short axial length, and a high risk of angle-closure glaucoma.

Younger onset age, being refractory to intraocular pressure (IOP) control, and 100% penetrance of malignant glaucoma after trabeculectomy make it a huge challenge in the management of refractory glaucoma in patients with Best disease.

The purpose of this study is to compare the surgical outcome of triple surgery and single trabeculectomy in each patient with Best disease.

What was learned from the study?

The triple surgery, Phaco + IOL implantation–trabeculectomy–anterior pars plana vitrectomy (PPV), yielded excellent results in lowering IOP, maintaining the visual function, deepening the anterior chamber, and avoiding the complication of malignant glaucoma.

The resolution of malignant glaucoma can be achieved by the surgery of phacoemulsification–IOL implantation–anterior PPV with successful lowering of IOP and reforming of the anterior chamber.

The vitreous may play a vital role in the mechanism of angle-closure glaucoma in patients with Best disease.

Introduction

Autosomal recessive bestrophinopathy (ARB), with homozygous or compound heterozygous sequence variants in BEST1, was first recognized by Burgess et al. [1] in 2008, with a high risk of angle-closure glaucoma (ACG). Angle closure with or without glaucoma was reported to affect around 29–71.4% of patients with ARB, the rate of which was much higher in Chinese patients [1,2,3,4]. The cause behind the simultaneous occurrence of ACG in BEST1-associated retinopathy, referred to as bestrophinopathies [5], including ARB and Best vitelliform macular dystrophy (BVMD), had not yet been elucidated.

Yttrium–aluminum–garnet laser peripheral iridotomy alone was not enough to reduce intraocular pressure (IOP) in patients with ARB with narrow anterior chamber [2]. Most reports agreed that a cataract extraction also failed to open the anterior chamber angle to a sufficient degree so that IOP was still high [2, 6, 7], despite a single case with controlled IOP, but required continued use of two topical medications after lens extraction [8]. Zhong et al. [7] also reported a unique case of a 26-year-old woman diagnosed with ARB and ACG without any improvement of the anterior structure by combined phacoemulsification, intraocular lens implantation, and goniosynechialysis, but benefit from additional low-dose transscleral cyclophotocoagulation (TCP) that ends with a lower IOP and a deepened anterior chamber in both eyes. The authors analyzed the reason for success: anterior vitreous liquefaction generated by post-TCP inflammation subsequently decreased vitreous integrity, absorbed the force from choroidal expansion, and increased flow conductivity through the vitreous cavity [7]. It indicated that the vitreous is intimately involved in the pathogenesis of the shallow anterior chamber in those patients. In addition to the younger age, solid and unliquefied vitreous presumably induce high posterior pressure, which is also confirmed during the surgery (personal perspective). The forward force potentially accelerates the development of narrow anterior chamber and even complete angle closure. This assumption is strengthened by our observation of 100% surgical success rate after triple surgery, while 100% penetration to MG after trabeculectomy alone inevitably increases the pressure gradient between the anterior and posterior segments. It is hereby especially emphasized that removal of the anterior vitreous is an indispensable procedure for patients with ACG and BEST1 mutation.

Malignant glaucoma is a serious complication after glaucoma filtering surgery, often with elevated IOP, but may also present with normal IOP, given the presence of an alternative aqueous outflow pathway. Although the exact mechanism of MG is not fully understood and may be multifactorial, the principle of management was clear: eliminate the pressure gradient between anatomic compartments and introduce communication between the posterior and anterior segments of the eye. The role of choroidal expansion has also been described [11]. In the present study, all five eyes with MG after trabeculectomy alone did not respond to medical management, including antiglaucoma medications and strong cycloplegics. It is reported that 14–50% of MG can be resolved with only medical therapy [12, 13]. The resolution of MG was finally achieved by the following surgery of phacoemulsification–IOL implantation–anterior PPV with successful lowering IOP and reforming of the anterior chamber. Our results provided an effective treatment algorithm for refractory MG in patients with BEST1 mutation. It showed that vitrectomy was required in those cases, potentially relieving the peripheral vitreous pressure, restoring the orientation of the ciliary body, and deepening the anterior chamber. Even the five eyes that experienced MG after trabeculectomy and following secondary surgery also achieved a good outcome compared to the other eyes that succeeded by triple surgery for the first time. A combined approach to simultaneously address all conditions would be advantageous to patients in terms of reduced costs and potentially faster visual recovery.

A single case (PPV + glaucoma drainage implant) without lens extraction shown by Low et al. [6] achieved a good outcome. However, clear lens/cataract extraction and IOL implantation were performed in all eyes in the present study. Removing the lens may largely deepen the anterior chamber and potentially reopen the angle, which is definitely beneficial to maintain the physiologic trabecular aqueous outflow since the filtering pathway is possibly no longer functional during their subsequent long life. We also encountered a case with a very early phase of ACG (not shown in this study) that underwent phacoemulsification, IOL implantation–goniosynechialysis–anterior PPV (without trabeculectomy), ending with deep anterior chamber and normal IOP. However, the therapeutic role of lens/cataract extraction in patients with ACG and BEST1 mutation needs to be clarified in future studies.

Young patients with angle closure are very rare [14]. Recently, Gao et al. [15] reviewed a large number of Chinese patients with ACG from 15-year records in a single center. The etiologies other than primary ACG could be identified in a large number of cases (67.4%). More comprehensive examinations are needed, especially fundus examinations, to exclude any secondary causes. Even with patients with ACG older than 40 years, especially combined with a fundus lesion such as “macular edema” in OCT, the differential diagnosis of ARB or BVMD with age-related macular degeneration and chorioretinitis can be challenging. Genetic analysis should be performed in suspect cases.

The application of mitomycin C during trabeculectomy remains the gold standard for glaucoma surgery, especially in China, since Asian patients appear to have a greater scarring response and are more susceptible to bleb failure compared to Caucasian patients [16]. The dose and duration of mitomycin C of 0.4 mg/ml and 2–3 min is very common in China [17]. Increasing the exposure time of mitomycin C can be adapted for younger patients who are known to have a greater wound healing capacity. In general, the surgical outcome can be influenced by the dose of mitomycin C, with higher rates of hypotony after higher concentration or/and duration. However, this complication was not found in any of our patients. Compared to our study, Zhong et al. applied a lower concentration of mitomycin C and a shorter exposure time which may indicate that the failure of single trabeculectomy in patients with ARB may not be related to mitomycin C dosing.

Limitations of our study should be discussed. First of all, there were two patients who underwent trabeculectomy at other local hospitals, so one may be concerned that the surgical outcome is influenced by the different levels of glaucoma specialists. However, trabeculectomy was also performed at the local tertiary eye center on these two patients, and according to the medical record, surgical procedures, including mitomycin C dose, were also similar to those of our hospital. Previous studies showed that the results of trabeculectomy performed by residents or trainees can also have a high success rate [18, 19]. We believed that the failure after single trabeculectomy in patients with ARB may not be affected by the different surgeons. Second, there was a possibility of bias between two eyes in each patient since trabeculectomy was always performed first in the eyes with usually earlier onset of ACG than in the other eyes, even though there were no significant differences in all ocular parameters between those two groups. Third, the follow-up time of patients was variable, and only two patients had a long-term follow-up after triple surgery. Long-term observations in those eyes with triple surgery should be addressed. Fourth, the EOG was not performed on all patients. However, multimodal imaging and genetic analysis can also support the diagnosis. The clinical diagnosis of ARB was also confirmed in one patient without genetic testing by a panel of retinal specialists. Fifth, the number of cases was relatively small. The condition in which the secondary ACG and ARB combined is very rare. In addition to that, the strict criteria that met the self-controlled study design also limited the number of enrollees. Sixth, the natural retrospective designs lead to a lack of preoperative and postoperative anterior segment photographs of the anterior chamber.

Conclusions

This self-controlled series study clearly showed that triple surgery is superior to single trabeculectomy for patients with ACG and BEST1 mutation in terms of IOP control, maintenance of visual function, and deepened anterior chamber, effectively bypassing the complication of MG. The role of the vitreous is complicated in the mechanism of ACG and the high incidence of MG after filtering surgery, together with the younger age, short AL, and shallow anterior chamber. Trabeculectomy was not a contraindication but is strongly recommended in combination with removal of the anterior vitreous in the management of patients with ACG with BEST1 mutation. MG can be successfully managed by appropriate and timely interventions.