Phaco-UCP; combined phacoemulsification and ultrasound ciliary plasty versus phacoemulsification alone for management of coexisting cataract and open angle glaucoma: a randomized clinical trial

Background Various surgical techniques have been described, to be combined with cataract surgery in glaucoma patients, aiming for an additional reduction of intraocular pressure (IOP), hence minimizing the burden of anti-glaucoma medication (AGM). Ultrasound ciliary plasty (UCP) is a recent microinvasive glaucoma surgery (MIGS) recommended for primary and refractory glaucoma. This study was conducted to evaluate the safety and efficacy of a new technique; combined phacoemulsification and ultrasound ciliary plasty (Phaco-UCP) as a primary surgical treatment for coexisting cataract and open angle glaucoma. Methods A randomized clinical trial, including 61 eyes of 61 patients with visually significant cataract and open angle glaucoma, randomized to either Phaco-UCP (study group; 31 eyes) or phacoemulsification alone (Phaco-alone) (control group; 30 eyes). Primary outcomes included reduction in IOP and/or the number of AGM. Secondary outcomes included visual acuity improvement and complications. Qualified Success was defined as an IOP reduction ≥ 20% from baseline value, with an IOP 6–21 mmHg, with no additional AGM or glaucoma surgery. Failure was defined as either < 20% IOP reduction, despite AGM use, the need of glaucoma surgeries or serious complications. Results At 18 months postoperatively, Phaco-UCP group had a median IOP reduction of 7 mmHg (Q1, Q3 = 3, 10) compared to 2 mmHg (Q1, Q3 = 2, 3) in Phaco-alone group (P < 0.001). Phaco-UCP group had significantly higher success rate at all time points reaching 67.7% at the last follow-up versus 16.7% only in Phaco-alone group (P< 0.001). The median number of AGM significantly decreased from [3 (Q1, Q3 = 2, 4), 3 (Q1, Q3 = 2,3)] respectively, (P =0.3)] at baseline to [1 (Q1,Q3 = 1, 2), 2 (Q1,Q3 = 2, 2)] respectively, (P < 0.001)] at 18 months postoperatively. No serious intraoperative or postoperative complications were encountered in either group. Conclusion Phaco-UCP is a simple, safe and effective procedure for management of coexisting cataract and open angle glaucoma. Trial registration ClinicalTrials.gov identifier, NCT04430647; retrospectively registered. June 12, 2020.


Background
Cataract and glaucoma are leading causes of blindness all over the world (51 and 8%, respectively), that frequently coexist in the same eye [1]. Cataract surgery has been found to decrease the intraocular pressure (IOP) in both normal and glaucomatous eyes, by an average of 1.5-4 mmHg [2,3]. However, this reduction is influenced by many factors including preoperative IOP, angle configuration and type of glaucoma [4]. IOP reduction is more with higher preoperative IOP [2] and in eyes with closed angles more than those with open angles [4]. In eyes with moderate to advanced open angle glaucoma, relying on phacoemulsification alone to reduce IOP may not be sufficient. In addition, the effect of IOP reduction after phacoemulsification alone is known to regress over time [5]. Moreover, IOP spikes after phacoemulsification is one of the feared complications in moderate and advanced stages of glaucoma [6].
Many glaucoma surgeons recommend a combined procedure for patients with significant cataract and glaucoma requiring urgent drainage surgery [7]. Phaco-trabeculectomy (Phaco-trab) has been traditionally shown to be effective, but might be associated with significant complications, the commonest of which are hypotony, hyphema, and shallow anterior chamber [8]. Recently, various microinvasive glaucoma surgeries (MIGS) have been described, to be combined with cataract surgery, aiming for an additional reduction of IOP and hence, decreasing the burden of antiglaucoma medication (AGM) [9].
Ultrasound ciliary plasty (UCP) is a recent nonincisional technique recommended for primary and refractory glaucoma [10,11]. It involves inducing selective coagulation of the ciliary epithelium using the high intensity focused ultrasound technology (HIFU) [10]. It has the advantages of being easy, one-step, highly reproducible, and more precise treatment [12].
This study was carried out to evaluate the safety and efficacy of combined phacoemulsification and Ultrasound ciliary plasty (Phaco-UCP) as a first-line surgical treatment for coexisting cataract and open angle glaucoma, compared to phacoemulsification alone (Phacoalone). To our knowledge, this is the first report of the results of combined Phaco-UCP.

Study design
This was a randomized clinical trial, conducted at ophthalmology department of Dar Al Shifa hospital, Kuwait during the period from September 2018 through March 2020 after local "Institutional Review Board" approval. A written informed consent was obtained from each patient after explanation of the study nature. The study protocol was adherent to the tenets of the Declaration of Helsinki and to CONSORT guidelines for reporting clinical trials. The study was retrospectively registered on www.clinicaltrials.gov (NCT04430647) available at https://www.clinicaltrials.gov/ct2/show/NCT0443064 7?cond=NCT04430647&draw=2&rank=1.

Sample size
Sample size was calculated using Epi Info™ software (CDC, version 7.2.3.0). The significance level (α) and the statistical power were set at 0.05 and 0.80 respectively. To our knowledge, no previous study compared Phaco-UCP and Phacoemulsification alone. Therefore, the effect size was calculated based on the difference in proportions of successful reduction of IOP, reported in a previous study comparing combined phacoemulsification and Endoscopic cyclophotocoagulation (Phaco-ECP) and phacoemulsification alone [13], (7.5% in control group and 37.5% in the study group at 6 months postoperative). We assumed that Phaco-UCP can achieve the same success rate of Phaco-ECP. Using Fleiss method and assuming a 1:1 ratio of groups, the total calculated sample size was 60 (30 per group). Ten percent expected attrition was added to the sample size to account for loss to follow-up, so the final sample size was 66 patients (33 per group).

Inclusion/exclusion criteria
Patients with primary open angle glaucoma (POAG) or pseudoexfoliation glaucoma with coexisting visually significant cataract that required phacoemulsification were included. Visually significant cataract was defined, according to LOCS III criteria as: nuclear cataract ≥ 3/6.9, cortical cataract ≥3/5.9 or posterior subcapsular cataract ≥ 2/5.9 [14]. POAG was defined as optic neuropathy with typical glaucomatous optic disc cupping and visual field changes together with an open angle (Shaffer grade 3 or 4). Pseudoexfoliation glaucoma was diagnosed if there was exfoliation material adherent to the lens surface or to the pupillary margin, wide-open angle with dense pigmentation, Sampaolesi's line, and an optic neuropathy with matching visual field loss. Glaucoma severity was classified based on visual field mean deviation (MD) into mild (MD better than − 6 dB), moderate (MD − 6 dB or worse but better than − 12 dB) and advanced (MD is − 12 dB or worse) [15]. Only eyes with mild and moderate glaucoma were included. For patients who had both eyes operated, only one eye was included in the study. Patients with any other type of glaucoma; including narrow angle glaucoma, neovascular, uveitic or angle recession glaucoma, patients with advanced glaucoma and patients with history of glaucoma surgery, intraocular surgery, laser trabeculoplasty, laser refractive surgery or any ocular diseases that would affect safety or interfere with the procedure were all excluded. We also excluded patients who declined to participate as well as those with incomplete follow-up or missing data.

Randomization and masking
Patients were assigned by simple coin flip randomization for either combined phacoemulsification and ultrasound ciliary plasty (Phaco-UCP; the study group), or phacoemulsification alone (Phaco-alone; the control group). The random allocation sequence was generated by one of the authors (EAA). Allocation assignments were sealed in opaque envelopes labelled only with study identification numbers. Patients were enrolled and assigned to intervention by the same author (YAA). Patients were not blinded to the intervention, as they had to sign a written informed consent. All preoperative and postoperative assessments were performed by the same author (MAT), who was masked to group allocation.

Surgical technique
All surgeries were performed by the same surgeon (YAA).

Phaco-UCP
Under peribulbar anesthesia, using 2% lidocaine (Xylocaine 2%, AstraZeneca, Bangalore, India), UCP was performed first, followed by phacoemulsification. UCP was performed using the same technique described before [16]. For all treatments, 2nd generation probe was used (EyeOP1, Eye Tech care; France) with the same parameters: operating frequency was 21 MHz; number of sectors activated was 6; Acoustic power was 2.45 W; duration of each shot was 8 s; and the time between shots was 20s. Using this protocol, no more than 3 min would be added to the Phaco-time. The probe diameter (11, 12 or 13 mm) was determined according to the eye's biometric readings. The coupling cone was centered on the eye and kept in place with low vacuum suction, followed by introduction of the treatment probe inside the cone, then activation of the transducers by constantly pressing the foot switch. Once UCP treatment was finished, phacoemulsification was commenced.

Phacoemulsification
A standard phacoemulsification was performed with 2.2 mm clear corneal incision, continuous curvilinear capsulorhexis, phacoemulsification and implantation of foldable acrylic intraocular lens (AcrySof® IQ SN60WF monofocal; Alcon Laboratories Inc., Fort Worth, TX, USA) in the capsular bag. Irrigation-aspiration was performed for at least 30 s to remove any viscoelastic from the anterior chamber. Reformation of the anterior chamber was done with balanced saline solution (BSS), followed by hydration of the corneal wound and side port. Intracameral cefuroxime (AproKam®) and subconjunctival dexamethasone injection were used at the completion of surgery.

Postoperative management
Follow-ups were scheduled at 1 day, 1 week, 1 month, 3 months, 6 months, 12 months and 18 months postoperatively. Patients were treated with moxifloxacin 0.05% eye drops six times daily for 1 month and prednisolone acetate 1% eye drops six times daily for 1 week followed by gradual withdrawal over 4 weeks. Preoperative antiglaucoma medications were continued during the first postoperative month, and then gradually decreased at each subsequent visit if the IOP was maintained at the target level. They were added only if IOP exceeded 21 mmHg or when they were needed to treat visual field or optic nerve changes.

Outcome measures
Primary outcome measures included reduction in IOP and/or the number of AGM. Secondary outcome measures included CDVA improvement, intraoperative and postoperative complications.

Success and failure rates
Qualified Success was defined as an IOP reduction of at least 20% from baseline value, with an IOP that is between 6 and 21 mmHg, without the need for additional AGM or glaucoma surgery [13,17]. Failure was defined as either < 20% IOP reduction form baseline value, despite the use of antiglaucoma medications, the need of other glaucoma surgeries or the development of any serious complications. By serious complications, we mean hyphema or vitreous hemorrhage necessitating surgical intervention, choroidal hemorrhage, chronic uveitis, endophthalmitis, hypotony (IOP ≤ 5 mmHg), phthisis, intraocular lens dislocation, and retinal detachment.

Statistical analysis
Data were tabulated and statistically analyzed using the Statistical Package for Social Sciences (SPSS) version 25. Qualitative data were described as numbers and percentages. While quantitative data were described as means (± SD) or medians (first and third quartiles: Q1, Q3). Shapiro-Wilk test was used to test normality. Betweengroups comparison was done using Student t-test for normally distributed data like age and CDVA and Mann-Whitney U test for non-normally distributed variables. Within-group comparisons were done using Wilcoxon signed rank test and Freidman test. "P value ≤ 0.05" was considered to be statistically significant.

Patients' characteristics
A total of 61 eyes of 61 patients were randomly distributed into two groups: the study group (Phaco-UCP), including 31 eyes and the control group (Phaco-alone), including 30 eyes (Fig. 1). No statistically significant differences were found between the two groups regarding demographic and baseline clinical characteristics (Table 1). Table 2 compares the preoperative and postoperative IOP between the two groups. Both groups had a significantly lower IOP postoperatively. A significantly greater IOP reduction and percentage IOP reduction were observed in the study group compared to the control group at all-time points (Tables 3 and 4 respectively). Figure 2 shows comparison of median IOP in both groups at different time points, while Fig. 3 shows boxplot for the median IOP at 18 months postoperative in both groups. The study group had a significantly higher success rate compared to the control group at all-time points, reaching 67.7% at the last follow up in the study group versus 16.7% only in the control group (Table 5).

Safety and complications
All patients of the study group tolerated the procedure well with no serious intraoperative or postoperative complications ( Table 7). The most frequent postoperative complication was anterior chamber flare, which occurred in all eyes and was treated by increasing the frequency of topical steroids with the help of Non-Steroidal Anti-inflammatory (NSAIDs) eye drops and resolved completely over 3-4 weeks. Three eyes (9.6%) developed fibrinous reaction, which resolved completely over 3-4 weeks with the use of the same regimen. Mydriasis occurred in 3 eyes (9.6%) and resolved spontaneously after 6 months. Clinically significant macular oedema (CME) developed in four eyes (12.9%). However, it was transient and resolved after one month with NSAI Ds drops four times a day, without affecting the final   In the control group, 3 patients (10%) had anterior chamber inflammation, 3 patients (3.3%) developed cystoid macular oedema, and one patient (3.3%) developed hyphema. All these complications resolved by appropriate treatment within 4 weeks of surgery.

Discussion
Ultrasound ciliary plasty (UCP) is a noninvasive IOPlowering technique that uses high-intensity focused ultrasound (HIFU) to achieve selective coagulation of the ciliary body, with a more predictable and controlled IOP reduction than traditional cyclodestructive procedures [10,18]. Although its main IOP-lowering mechanism is reduction in aqueous humor inflow following ciliary epithelial thermal coagulation, an increase in suprachoroidal and transscleral aqueous humor outflow has also been reported [10,19,20]. Therefore, It has  been used by many glaucoma surgeons for different types of glaucoma [10-12, 21, 22]. In our previous study [16], we reported the safety and efficacy of UCP as an initial treatment for primary and secondary open angle glaucoma. In the current study, we report the outcomes of a new combined procedure (Phaco-UCP) as a primary surgical treatment for coexisting open angle glaucoma and visually significant cataract, compared to phacoemulsification alone (Phacoalone). We found that combining UCP with phacoemulsification resulted in significantly greater reduction of IOP and number of AGM than phacoemulsification alone, without jeopardizing the final visual acuity. To our knowledge, this is the first report of Phaco-UCP, so we will compare its results to those of combined phacoemulsification and endoscopic cyclophotocoagulation (Phaco-ECP), a well-known cyclophotocoagulation procedure, which provides selective destruction of ciliary body epithelium with less tissue disruption [23].
Francis et al. [13] reported that after a follow up period of 3 years, Phaco-ECP resulted in lower IOP and a greater reduction in AGM than Phaco-alone at all time points. However, they reported lower percentage IOP reduction, and lower success rates in both the study and control groups (percentage IOP reduction at 2 years 10.1 ± 17.1% and 0.8 ± 12.0% respectively and success rates at 2 years 13.8 and 3.8% respectively) than reported in the current study, most probably due to different study population. Their study included medically controlled POAG patients with a lower baseline IOP (18.1 ± 3.0   mmHg in both groups) and fewer number of AGM used preoperatively (1.5 ± 0.8, 2.4 ± 1.0 in the study and control groups respectively). In a retrospective study by Pérez Bartolomé et al. [24], comparing Phaco-ECP to Phaco-alone in patients with POAG, success rate after one year for Phaco-ECP (69.6%) was similar to that reported in the current study (71%), yet with a lower percentage of IOP reduction (21.5%) compared to the current study (36%). Their Phaco-ECP group included patients with uncontrolled glaucoma, with previous failed surgery and 3 or more AGM. Interestingly, their Phaco-alone group had a comparable IOP reduction (1.9 ± 3.6 mmHg) and percentage IOP reduction (9.9 ± 7.5%) to our control group, however, with a higher success rate (40%). This might be due to the fact that patients in their Phaco-alone group had medically controlled early POAG with a lower baseline IOP (18.4 ± 3.7 mmHg), with one or two preoperative medications only.
Regarding safety, the less invasive nature of UCP made it possible to avoid the serious complications of traditional filtering surgery and implant-related complications of MIGS. The most common postoperative complication of Phaco-UCP encountered in our study was the anterior chamber reaction in the form of aqueous flare, seen in all treated eyes, starting at day one post-operatively and resolving over 3-4 weeks with intensive frequent topical steroid therapy and NSAIDs. Previous studies have reported significant increase of anterior chamber flare on the first day after UCP, followed by a gradual decrease, to recover to preoperative levels by 3 months postoperatively [22,25]. However, the increased flare values after UCP were lower than those recorded after traditional cyclophotocoagulation [26]. Intraocular inflammation after UCP has been attributed to direct damage of ciliary epithelium, which is the key component of blood-aqueous barrier. Similarly, its resolution is proposed to follow the gradual recovery of blood-aqueous barrier, hence UCP was considered safe [22]. Moreover, the intraocular inflammation has been suggested to play a role in IOP reduction after cyclodestructive procedures [27,28], due to release of some inflammatory mediators like prostaglandins, which enhances the uveoscleral aqueous outflow [29].
We reported a similar incidence of postoperative transient macular oedema for Phaco-UCP (12.9%) and Phaco-alone (10%), (P = 0.7). Hugo et al. [25] also reported a similar incidence (13%) after UCP alone. Mydriasis occurred in 3 eyes (9.6%) after Phaco-UCP and disappeared at the 6th month postoperative. Many authors have noticed changes in pupil shape and dynamics after UCP, both in phakic and pseudophakic eyes. Though a consensus has not been reached concerning the mechanism, this has been reported to be temporary and to resolve spontaneously after variable duration [16,[30][31][32].
In our hands, no serious complications occurred after Phaco-UCP. We observed that postoperative complications of combined Phaco and UCP were similar to those of UCP alone [10,12,21,25]. For patients with coexistent open angle glaucoma and visually significant cataract, this combined procedure seems to be a better choice than phacoemulsification alone. Moreover, it may offer many advantages than the traditional phaco-trabeculectomy procedure. The easier technique of UCP allows for a shorter operation time and of course less postoperative complications. In addition, Phaco-UCP needs fewer postoperative follow-ups and additional interventions (including subconjunctival injection of 5-FU and laser suture lysis). Phaco-UCP might provide a temporary control of IOP in patients anticipating a future filtering surgery, until the ocular condition has improved enough to allow surgery. The option of repeated treatment with this non-invasive procedure (UCP) makes it feasible, effective and safe option in glaucoma management.
One of the limitations of our study is applying a simple randomization method, in the setting of a small sample size, which might yield unequal number of patients in each group, with different baseline characteristics, resulting in unreliable interpretation of results. However, we had nearly equal, matching groups regarding baseline characteristics. Another limitation is the short duration of follow-up (18 months), probably not reflecting the long-term outcome of the procedure. Future studies with larger samples, longer follow-up periods and stronger randomization techniques would be valuable to achieve more robust conclusion about the long-term efficacy of Phaco-UCP. Finally, this study was carried out on Asian population only. Racial differences may influence pigmentation of ocular structures including the ciliary epithelium, consequently enhancing or compromising Phaco-UCP effect [33]. The efficacy and safety of Phaco-UCP procedure in other ethnicities should be further evaluated.

Conclusion
This is the first report of the novel technique of Phaco-UCP. The favorable findings of this study suggest that combining UCP to phacoemulsification does not compromise the phacoemulsification results and at the same time provides acceptable IOP control.