The Effect of Combined Phacoemulsification and Endo-Cyclophotocoagulation on Intraocular Pressure Fluctuation Assessed by the Water Drinking Test in Patients with Primary Open Angle Glaucoma

Glaucoma is a chronic progressive disorder of the optic nerve and is the commonest cause of irreversible blindness globally. The estimated number of glaucoma patients in 2020 is 76 million, and this number is predicted to increase to almost double to 111.8 million by 2040 [1]. Glaucoma is characterised by distinctive structural damage to the optic disc with corresponding visual field defect. In adults, it is broadly classified into primary and secondary glaucoma with further division into open or closed angle glaucoma.

The mainstay of treatment is to lower the intraocular pressure (IOP) to a level at which further glaucomatous damage is unlikely to occur. Reduction in IOP can be achieved by either reducing the aqueous production or increasing its outflow. Treatment options include medical, laser, and surgical therapy.

Endoscopic cyclophotocoagulation (ECP) uses 810 nm diode laser to ablate the pars plicata of the ciliary body. Direct visualization enables the treatment to be targeted to the ciliary body epithelium and avoid damage to adjacent tissues as seen in trans-scleral cyclophotocoagulation [2]. Histologically, contraction of the ciliary process and disruption of the ciliary epithelium with sparing of the ciliary muscle and sclera are seen after ECP [3, 4]. This reduces aqueous production and lowers the IOP.

ECP is considered one of the minimally invasive glaucoma surgeries that can be combined with cataract surgery in treating patients with significant cataract and glaucoma. Berke found that glaucoma patients who underwent combined phacoemulsification and ECP had a 3 mm Hg reduction in IOP and IOP-lowering medication, while phacoemulsification alone had no change in IOP [5].

The role of diurnal IOP fluctuation in glaucoma progression was investigated when some patients still progressed despite controlled IOP seen during clinic visits. Asrani et al. [6] in a prospective study found that large diurnal IOP fluctuation is a strong independent risk factor for disease progression, indicating the large IOP range at which the eye is exposed to outside of clinic visits and hence not addressed during treatment [7]. Drance found that treated primary open angle glaucoma (POAG) patients with apparently controlled IOP had a mean IOP variation of 7.5 mm Hg, while those not on any treatment had a mean variation of 12.5 mm Hg as opposed to a normal group that had a variation of only 5.5 mm Hg [8].

The water drinking test (WDT) is a provocative test that can detect the peak and fluctuation in IOP. An amount of water, usually 1 L or 10 mL/kg, is ingested over 5–15 min, followed by quantification of IOP rise. Previous studies have shown that by ingesting a bolus of fluid over 5 min, the peak IOP during WDT correlates with the peak IOP obtained by diurnal testing and modified diurnal tension curve [9‒11]. Patients with worse mean deviation on visual field had higher IOP peaks and fluctuation after WDT, and higher IOP peaks are predictive of future visual field progression [12, 13].

WDT has also been used to assess the effectiveness of treatment. Comparisons have been made for various topical medications, between medical and surgical treatment, and also for laser treatment [14‒16]. Kerr et al. [14] found that SLT reduces the peak and fluctuation in IOP during WDT. Although the IOP-lowering effects of combined phacoemulsification and endo-cyclophotocoagulation (phaco-ECP) on POAG patients have been established, the effect on IOP fluctuation is still unknown [17, 18]. We aimed to determine the effect of phaco-ECP on baseline and peak IOP and IOP fluctuation, as assessed by the WDT. We postulated that WDT post phaco-ECP will show a reduction in baseline, peak, and IOP fluctuation alongside reduced aqueous production.

This was a prospective observational study conducted from April 2019 to February 2021. Patients with POAG on follow-up at the ophthalmology clinic, Universiti Kebangsaan Malaysia Medical Centre (UKMMC), who fulfilled the inclusion and exclusion criteria, were recruited. This study adhered to the tenets of the Declaration of Helsinki and ICH guideline for good clinical practice. Ethical approval was obtained from the Medical Research and Ethical Committee, UKM (UKM PPI/111/8/JEP-2018-672), and written informed consent was obtained from all participants.

A sample size of 21 eyes was calculated based on a difference in 0.3 mm Hg of IOP fluctuation before and after ECP to achieve a power of the study of 90% at the < level of 5% (PS Power and Sample Size Calculations version 3.1.2) [14]. The inclusion criteria were patients above 50 years old, to ensure that we did not include younger patients who may fall under juvenile open angle glaucoma and who may behave differently in terms of IOP control; were diagnosed with POAG and treated with topical antiglaucoma medications; and were planned for combined phacoemulsification surgery plus ECP. The indication for ECP was to reduce the number of topical antiglaucoma medications. POAG was diagnosed based on open angle on gonioscopy, glaucomatous optic disc changes which include increased vertical cup-to-disc ratio of ≥0.7, rim notching or thinning, with reproducible visual field defect on Humphrey visual field test (Humphrey, Zeiss Inc.), and no other secondary causes were found. Patients who had trabeculectomy, glaucoma drainage device, or laser trabeculoplasty were excluded. Those who had active infection or inflammation, or could not tolerate the WDT because of fluid restriction, end-stage renal failure, congestive cardiac failure, and urinary retention, were also excluded. Patients who later had intraoperative complications during phaco-ECP were also excluded. Data collected include age, gender, the number of antiglaucoma medications, medical and ocular history, best corrected visual acuity using the Snellen chart (Hamblin, London, UK), anterior segment examination using a slit lamp biomicroscope, and optic nerve evaluation using a superfield lens (Volk, OH, USA). The IOP was measured using the Goldmann applanation tonometer.

The patient was required to fast from any food or fluid for at least 2 h prior to WDT. Prior to surgery, baseline IOP was measured followed by ingestion of 10 mL/kg of water within 5 min. This quantity of water is chosen to allow tolerability of the test in the elderly population compared to other methods of WDT [19]. The IOP was measured by an operator who would operate and dial the Goldman tonometer mounted on a slit lamp and record the results while the reader read. Three measurements were measured and averaged and repeated if the difference in reading was >2 mm Hg. IOP was measured at 15, 30, 45, and 60 min after water ingestion. The baseline IOP (IOP measure just before water ingestion), peak IOP (highest IOP recorded after water ingestion), IOP fluctuation (the difference between the peak and baseline IOP), and mean IOP (the mean of the four IOP measurements) were then calculated. IOP fluctuation was considered significant if the difference is ≥6 mm Hg [16].

Surgery was performed by two glaucoma consultants and one glaucoma fellow. Phacoemulsification was performed under local anaesthesia via a clear corneal incision, and an intraocular lens was implanted into the capsular bag. This was followed by ECP using the endo-optics machine (Endo Optiks E2 Ophthalmic Endoscopy System) before viscoelastic was removed. If phacoemulsification was complicated, ECP was not performed, and the patient was excluded. Cohesive viscoelastic was used to deepen the anterior chamber, and treatment was commenced using a curved probe via the main incision. The treated area of the ciliary process was between 180 and 270°, depending on the severity of glaucoma, number of IOP-lowering medications, and baseline IOP. The laser machine was put on continuous mode with a power of 150–200 mW, and laser was applied until whitening and shrinkage of the ciliary processes were seen. Residual viscoelastic was then removed, and watertight wound was ensured either by wound hydration or 10/0 nylon sutures. Intracameral cefuroxime 1.0 mg/0.1 mL was given at the end of the procedure.

Postoperatively, the patient was started on topical ciprofloxacin 0.3% and dexamethasone 0.1% two hourly for 1 week and tapered over 6–8 weeks. All antiglaucoma medications were tapered as early as 1 week postoperatively while maintaining clinic IOP reading of ≤18 mm Hg, based on the Advanced Glaucoma Intervention Study which found that persistent IOP reading of ≥18 mm Hg is a risk factor for progression [20]. Persistently high IOP was treated by adding antiglaucoma medications. A repeat WDT was performed at least 6 weeks after surgery as some patients were affected by the COVID-19 pandemic lockdown and the test had to be delayed by a few weeks.

Statistical analysis was performed using Statistical Package for Social Science, version 25.0 for Windows (SPSS Inc., Chicago, IL, USA). Normally distributed data were presented as mean and standard deviation, whereas nonparametric data were presented as median and interquartile range. Categorical data were expressed as frequencies and percentages. Within- and between-group changes in IOP were analysed using repeated measurement ANOVA. To compare IOP changes pre- and postoperatively, Wilcoxon signed-rank test was used. Multiple linear regression analysis was performed to evaluate the risk factors for IOP fluctuation. A p value of <0.05 was considered statistically significant.

A total of 24 eyes from 21 patients were recruited in the study. Four patients were excluded: 2 patients could not tolerate the WDT and 2 patients had complicated cataract surgery. The remaining 20 eyes of 17 patients were included in the final analysis.

The mean age was 73.4 ± 6.82 years old, and the mean weight was 67.07 ± 12.14 kg. Slightly more than half of the participants were Chinese (n = 11, 55%), followed by Malay (n = 7, 35%) and Indian (n = 2, 10%). There was equal distribution between the right and left eye (Table 1). The mean duration between the first and second WDT was 9.45 ± 3.78 weeks.

Repeated measurement ANOVA was performed to assess the mean IOP change after WDT (Table 2). We found significant change in IOP at various time points in both pre- and postoperative WDT. Preoperative WDT showed a significant mean IOP increase from baseline by 3.57 mm Hg (p < 0.001) at 15 min, by 4.15 mm Hg (p < 0.001) at 30 min, by 3.63 mm Hg (p < 0.001) at 45 min, and by 1.85 mm Hg (p = 0.002) at 60 min. However, IOP significantly reduced by a mean of 1.52 mm Hg (p < 0.001) from 30 to 45 min. The mean increase in IOP from baseline was 4.15 mm Hg (28.17% increment).

The postoperative WDT was repeated at least 6 weeks after surgery. We found significant mean IOP increase from baseline by 4.53 mm Hg (p < 0.001) at 15 min, by 5.85 mm Hg (p < 0.001) at 30 min, by 4.7 mm Hg (p < 0.001) at 45 min, and by 3.03 mm Hg (p < 0.001) at 60 min (Table 2). IOP also significantly reduced by 2.82 mm Hg (p = 0.001) from 30 to 60 min after the WDT. The mean increase in IOP from baseline was 5.9 mm Hg (39.5% increment).

While the postoperative IOPs were higher than the preoperative IOPs at all time points, we did not find significant differences in the IOPs at each point, possibly because of the small sample size making the study underpowered to show such a difference. However, the pre- and postoperative changes in mean IOP showed a similar rise in IOP until reaching the peak at 30 min before gradually declining (Fig. 1). The mean IOP and peak IOP were higher postoperatively, although not statistically significant (Table 3). However, there was a significant increase in postoperative IOP fluctuation from 4.6 ± 2.06 mm Hg to 6.4 ± 3.2 mm Hg, p = 0.015, although postoperative IOP-lowering medications were significantly lower from 2.2 ± 1.15 to 0.35 ± 0.93 medications, p < 0.001. Fisher’s exact test revealed more eyes had significant IOP fluctuation of ≥6 mm Hg postoperatively (11 eyes [55%] vs. 4 eyes [20%], p < 0.001). Of the 11 eyes that had significant postoperative IOP fluctuation, 9 eyes were on two or more IOP-lowering medications. All 11 eyes were on latanoprost 0.005%, 9 eyes (81.82%) were on timolol maleate 0.5%, 5 eyes (45.46%) were on brimonidine tartrate 0.2%, and 3 eyes (27.27%) were on brinzolamide 1%.

Risk factors contributing to postoperative IOP fluctuation were explored using multiple linear regression analysis. Factors included were age, preoperative IOP fluctuation, preoperative and postoperative medication count, treatment area, glaucoma severity, and time between surgery and postoperative WDT. After adjusting for other factors, for every 1 mm Hg increase in preoperative IOP fluctuation, postoperative IOP fluctuation increased by 0.69 mm Hg (β = 0.69, 95% CI = 0.38–1.58, p = 0.004) and for every 1 postoperative antiglaucoma medication prescribed, postoperative IOP fluctuation increased by 0.63 mm Hg after controlling for other factors (β = 0.63, 95% CI = 0.61–3.32, p = 0.008, Table 4).

IOP fluctuation has been considered an important factor for glaucoma progression. IOP measured in clinic may not represent the true IOP readings throughout the day. Performing a 24-h IOP phasing is cumbersome, requiring hospital admission and repeated IOP measurements. An alternative to this is either performing IOP phasing during daytime or doing a WDT to measure IOP fluctuation [21].

We evaluated multiple IOP parameters after WDT in our cohort of POAG patients scheduled for combined phaco-ECP. We found that baseline IOP was similar between pre- and postoperative WDT while achieving significant reduction in IOP-lowering medications. This result agrees with Waldman et al. [22] who treated their patients of African descent with phaco-ECP in a lesser area of between 120 and 180° of ciliary processes even though their baseline IOP was higher than ours. They found no significant reduction in IOP but significant reduction in IOP-lowering medication. Yip et al. [23] also studied the effect of phaco-ECP covering treatment area of 270° among Asians with various types of glaucoma and achieved a mean IOP reduction of approximately 5 mm Hg at 24 months. However, they reported visual acuity reduction in five out of 29 eyes (17.2%) with complications including hyphaema, bullous keratopathy, and iris burn. We chose a treatment area of between 180 and 270° because majority of our patients had a lower baseline IOP in the mid-teens and we wanted to avoid overtreatment and devastating complications. However, studies reporting efficacy of ECP treated in larger areas of between 270 and 360 in POAG and other types of glaucoma found more reduction in IOP and IOP-lowering medications after 1–3 years [18, 24]. We achieved reduction in IOP-lowering medications with no change in baseline IOP with lesser treatment area of 180–270°.

IOP fluctuation has been observed to vary with different glaucoma treatments. Kerr et al. [14] reported a reduction in IOP fluctuation as assessed by WDT in POAG and ocular hypertension patients after selective laser trabeculoplasty. Medeiros et al. [25] found POAG patients had lower IOP fluctuation of 1.4 ± 0.4 mm Hg after trabeculectomy compared to 3.7 ± 0.4 mm Hg in patients treated medically. The effect of topical antiglaucoma on IOP fluctuation has also been evaluated. When comparing the four common IOP-lowering medications, agents that enhance outflow facility, like prostaglandin analogues, have less IOP fluctuation than aqueous suppressants like β-blockers and carbonic anhydrase inhibitors [19]. Additionally, patients on more IOP-lowering medications had higher IOP fluctuation, agreeing with our findings, implying an inherent higher resistance in the outflow facility, requiring more medications to control the IOP [19]. These reports suggest that procedures which enhance the outflow facility, like SLT and trabeculectomy, reduce IOP fluctuation, whereas procedures which reduce aqueous production, like ECP and topical aqueous suppressants, do not reduce IOP fluctuation. This is in keeping with Brubaker’s theory that WDT is an indirect measure of the outflow facility, and the ability of the eye to recover from transient IOP rise depends on the outflow facility [11].

We found higher preoperative IOP fluctuation and more postoperative IOP-lowering medications to be independent risk factors for higher postoperative IOP fluctuation. Phaco-ECP is a safe and effective method to reduce both the IOP and number of antiglaucoma medications, especially in patients with significant cataract. Although ECP reduces the IOP and allows reduction in topical antiglaucoma, we found that it does not eliminate the IOP fluctuation and in fact results in more IOP fluctuation postoperatively. The possible explanation for this is perhaps the postoperative inflammation after phaco-ECP has resulted in some degree of angle damage and hence increased resistance in the outflow. Phaco-ECP is therefore less suitable for patients who have attained the target IOP, but glaucoma progression still occurs, presumably from large IOP fluctuations [26]. It is important to note that IOP-lowering medications that work on the outflow facility, such as a prostaglandin analogue and to a lesser extent, an alpha agonist, should be preferred, if the need arises, to benefit from the blunting effect of these medications on IOP fluctuation [27, 28].

Although we acknowledge that our sample size was relatively small, it is comparable to other reported phaco-ECP studies, and we decided not to increase our sample size after the increased postoperative IOP fluctuation surfaced. The non-standardised ECP technique, varying timeline of WDT performed, and the fact that glaucoma medications were reduced after ECP are other limitations that may affect IOP fluctuation, apart from other potential analysed relevant factors such as age, varying treatment area, and varying glaucoma severity.

In conclusion, we found that phaco-ECP did not reduce IOP fluctuation postoperatively. In patients whose aim is to blunt IOP fluctuation, the focus of treatment should be on procedures that increase the outflow facility rather than those that reduce aqueous production.

Dr. Amirah Mohammad Razali received a masters scholarship funded by Universiti Putra Malaysia.

Ethical approval was obtained from the Universiti Kebangsaan Malaysia Research and Ethics Committee (Ethical approval code: UKM PPI/111/8/JEP-2018-672). This study adhered to the tenets of the Declaration of Helsinki and Malaysian Guidelines for Good Clinical Practice (GCP). A signed written informed consent was obtained from all patients prior to enrolment. The authors affirm that human research participants provided informed consent for the publication of their data.

The authors have no conflicts of interest to declare.

Dr. Amirah Mohammad Razali received a masters scholarship funded by Universiti Putra Malaysia. The rest of the authors disclosed no relevant financial relationship. The sponsor organisation had no role in the design or conduct of this study.

Conceptualization: Amirah Mohammad Razali, Tang Seng Fai, Syed Zulkifli Syed Zakaria, Jemaima Che-Hamzah, Othmaliza Othman, and Norshamsiah Md Din; methodology, formal analysis, and investigation: Amirah Mohammad Razali, Syed Zulkifli Syed Zakaria, and Norshamsiah Md Din; writing – original draft preparation: Amirah Mohammad Razali; and writing – review and editing: Amirah Mohammad Razali, Tang Seng Fai, Syed Zulkifli Syed Zakaria, Tin Aung, Othmaliza Othman, and Norshamsiah Md Din.

All data generated or analysed during this study are included in this article. Further enquiries can be directed to the corresponding author.