Clinical and Experimental Ophthalmology 2009; 37: 842848 doi: 10.1111/j.1442-9071.2009.02134.

Original Article
Effects of postoperative cyclosporine ophthalmic emulsion 0.05% (Restasis) following glaucoma surgery
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Ghasem Fakhraie MD, Joao F Lopes MD, George L Spaeth MD, Juliana Almodin MD, Parul Ichhpujani MD and Marlene R Moster MD
Wills Eye Institute, Philadelphia, Pennsylvania, USA

ABSTRACT
Purpose: To determine if postoperative topical cyclosporine 0.05% has any benecial effect following trabeculectomy Methods: This was an interventional, randomized, prospective, double-masked clinical trial of 44 consecutive patients with uncontrolled glaucoma requiring ltration surgery. Ocular surface disease index questionnaire and comprehensive ocular exam, including Schirmers tear test 1, were performed. Patients underwent routine trabeculectomy, with or without phacoemulsication. The study group (n = 22) received cyclosporine 0.05%, and the control group (n = 22) received articial tears. Patients were evaluated at 1 and 6 months post surgery. Outcome measures were intraocular pressure, success rate, bleb appearance, ocular surface disease index, Schirmers tear test 1 and conjunctival inammation. Results: Thirty-nine patients completed the study (19 in the study group, 20 in the control group). The mean baseline intraocular pressure was 23.8 12. 6 mmHg in the study group and 25.9 10.6 mmHg in the control group (P = 0.513). Mean intraocular pressure at postoperative month 6 was 14.88 6.2 and 14.62 5.46 mmHg in the study group and control group, respectively (P = 0.837). There was no statistically signicant difference in the mean values

of Schirmers tear test 1 and the level of conjunctival hyperaemia between the two groups at baseline, months 1 and 6 post surgery. The treatment group had a statistically signicant decrease in ocular surface disease index score at 6 months (P = 0.003), indicating less severity of dry eye symptoms and signicant reduction in ocular pain. Conclusions: Topical cyclosporine 0.05% had no effect on postoperative bleb function and intraocular pressure following trabeculectomy, but improved subjective ocular surface symptoms in these patients. Key words: conjunctiva, cyclosporine A, inammation, trabeculectomy.

INTRODUCTION
Glaucoma ltering surgery occasionally fails because of postoperative scarring between the sclera, Tenons capsule and conjunctiva.14 Numerous antibrotic agents such as mitomycin-C (MMC) and 5uorouracil are used to modify the normal healing process. Although these agents increase the success of ltering surgery, alternatives are being explored because of the risks associated with their use. Cyclosporine A (CsA) is an immunomodulatory, anti-inammatory and antibroblastic agent. Its action inhibits calcineurin, which in turn controls the synthesis of proteins such as interlukin-2 involved in activation of CD4+ and CD8+ T cells.2 CsA also inhibits production of other lymphokines

Correspondence: Dr Marlene R Moster, Wills Eye Hospital Glaucoma Service, 840 Walnut Street, Suite 1140, Philadelphia, PA 19107, USA. Email: moster@willsglaucoma.org Received 10 June 2009; accepted 29 July 2009. Disclosure: The study was supported by an unrestricted educational grant from Allergan, Inc., Irvine, CA, USA. 2009 The Authors Journal compilation 2009 Royal Australian and New Zealand College of Ophthalmologists

Cyclosporine following trabeculectomy (interferon-g) and angiogenesis factors.510 Previous studies have proposed a role in glaucoma surgery for cyclosporine comparable to MMC, with a lower rate of severe complications.2,3,11 Benecial effects of topical CsA regarding the improvement of ocular surface signs and symptoms in patients with dry eye have also been recently reported.6,7,9 Considering the potential benecial effects of topical CsA, we conducted this study to evaluate the clinical effects of topical CsA 0.05% (Restasis, Allergan, Irvine, CA, USA) following trabeculectomy. Our primary objective was to evaluate the effects of topical CsA 0.05% on ltering bleb function in terms of intraocular pressure (IOP) reduction and success rate. The secondary objective of this study was to determine whether CsA 0.05% improved the signs and symptoms of chronic irritation commonly experienced in patients following trabeculectomy.

843 The ocular history included data on dose, duration and number of antiglaucoma medications. The Ocular Surface Disease Index (OSDI) questionnaire6,12 was administered at the time of enrolment (before surgery) and at months 1 and 6 of follow-up visits to assess quantitatively the severity of dry eye and its impact on vision-related function. In brief, patients were asked 12 questions in three different subscales; ocular symptoms (5 questions regarding sensitivity to light, gritty sensation, sensation of pain or soreness in the eye, blurred vision and poor vision), vision-related functions and limitations (4 questions regarding problems or difculties in reading, driving at night, working with a bank automated machine and watching television) and environmental triggers (3 questions regarding difculties in windy conditions, places or areas with low humidity and areas that are air conditioned). Each answer was scored based on frequency of symptoms using a 5-point scale from zero (no problem) to ve (signicant problem). Responses to all answers were then combined for a composite OSDI score ranging from 0 to 100, in which higher scores signify more severe symptoms. All patients received a comprehensive ocular examination including a 5-min Schirmers tear test 1 (STT1).13 STT1 was done by the clinical coordinator at baseline, months 1 and 6 following surgery. Intraocular pressure was measured in a masked fashion using a Goldmann applanation tonometer (Haag Streit, Bern, Switzerland) preoperatively and postoperatively on day 1, week 1, months 1 and 6. The amount of conjunctival inammation was assessed by slit-lamp biomicroscopy prior to application of study eye drops and at each postoperative visit. It was graded from zero to four with each subsequent stage showing greater conjunctival inammation, as described by Stewart et al.14 All patients were evaluated for presence and severity of supercial punctatae keratitis (SPK) by slit-lamp examination using Flourescein staining at baseline, and also, day 1, week 1 and month 1 postoperatively. Each patient received a score between zero (no SPK) and three (severe SPK). Bleb appearance was graded on day 1, week 1, months 1 and 6 after surgery. The Indiana Bleb Appearance Grading Scale (IBAGS)15 was used for morphologic classication of the ltering blebs. This system consists of four parameters: bleb height (H), bleb extent (E), bleb vascularity (V) and leakage with the Siedel test (S). Bleb appearance was also documented by digital photographs.

METHODS
This was an interventional randomized prospective double-masked clinical trial. The study protocol was reviewed and approved by the Institutional Review Board at Wills Eye Institute. The study was conducted in compliance with the tenets of the Declaration of Helsinki and HIPPA. The trial was registered, and the information is publicly available at http:// www.clinicaltrials.gov (NCT00405431). The study population included consecutive glaucoma patients of either gender at the Wills Eye Institute Glaucoma service planned for ltering surgery with or without phacoemulsication. Inclusion criteria were ability to participate and complete the study and absence of any exclusion criteria. Exclusion criteria were age less than 18 years, enrolment in any other clinical trial or surgery during the past 3 months and clinically signicant mental or psychiatric disability. Only one eye of eligible patients was included in the study. Forty-four patients were enrolled over a 9-month period. Written informed consent was obtained from each patient. Medications used during the study consisted of unit dose vials of unpreserved CsA ophthalmic emulsion 0.05% (Restasis, Allergan, Irvine, CA, USA) for the treatment group and articial tears (Refresh Endura, Allergan, Irvine, CA, USA) as carrier vehicle for the control group. Study vials were identical unit dose vials in identical containers used twice daily. Each patient received one vial per day for 6 months.

Study measures
A brief medical history was obtained along with demographic data at baseline and subsequent visits.

Enrolment
Qualied patients were assigned equally in one of two groups (R or E) using a random number table;

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Fakhraie et al.
Figure 1. The Consort Flowdiagram of the study. CsA, Cyclosporine A.

group R received CsA ophthalmic emulsion 0.05% and group E received articial tears. Both patient and surgeon were masked as to which drop was being administered. The patients were instructed to start the study drops on the rst postoperative day (day 0) and continue it for 6 months on a twice-daily regimen (Fig. 1).

clinical research coordinator. In addition to the study medications, all patients received steroid and antibiotic eye drops. Glaucoma medications were used throughout the study period as needed.

Outcome measures
The main outcome measures were IOP and success rate. Other variables evaluated were best corrected visual acuity (BCVA) measured by standard Snellen visual acuity chart and converted to LogMAR, OSDI and STT1, bleb appearance and amount of conjunctival inammation. Success at postoperative month 6 was dened as an IOP reduction of 30% or an IOP 21 mmHg without hypotony (IOP < 6 mmHg) and without reoperation including needling bleb revision.

Intervention
Shortly after the baseline visit, patients underwent standard trabeculectomy with or without phacoemulsication. Intraoperative antimetabolite was used under the conjunctival ap for all patients with the same duration and concentration (MMC 0.4 mg/mL for 1.5 min or 5-uorouracil 50 mg/mL for 5 min).

Follow up
During the follow-up period, patients were examined, and the questionnaires were completed by the

Statistical methods
A study power of 80% and an a-error of 0.05% were chosen in showing a 20% difference in the success

2009 The Authors Journal compilation 2009 Royal Australian and New Zealand College of Ophthalmologists

Cyclosporine following trabeculectomy rate between the two groups. Statistical analysis was performed using SPSS for Windows version 10.1 (SPSS Inc., Chicago, IL, USA). Intra-group and intergroup changes for continuous parametric variables were evaluated by the paired Students t-test and unpaired Students t-test, respectively. Intra-group and inter-group changes for continuous nonparametric variables were evaluated by the Wilcoxon Signed Rank test and MannWhitney U-test, respectively. A one-way between-groups analysis of covariance was conducted to compare the effect of two different treatments on postoperative 6 months IOP. Categorical data were compared by Chi-squared test or Fisher exact test. For all measurements, a two-tailed test was used and a P-value of <0.05 was considered signicant for measured variables.
Table 1. Patient characteristics and demographics Variable Gender Male Female Age (years) Mean SD Range Type of glaucoma POAG PACG PEXG NVG Others Race White African American Hispanic Asian Prior surgery Laser trabeculoplasty Trabeculectomy Phacoemulsication Others Total Baseline LogMAR BCVA Mean SD Range Baseline IOP (mmHg) Mean SD Range Baseline glaucoma medication Mean SD Range Type of conjunctival ap Fornix-based Limbal-based Antimetabolite Mitomycin-C 5-uorouracil Type of surgery First trabeculectomy Repeat trabeculectomy Triple procedure Treatment group (n = 19) 8 11 61.73 15.11 3988 10 4 2 2 1 10 8 1 0 5 1 0 4 10 0.58 0.69 02.2 23.8 12.6 1452

845

Control group (n = 20) 10 10 66.60 14.50 2789 11 3 3 1 2 11 5 1 3 8 0 1 3 12 0.36 0.48 02.2 25.9 10.6 1849

RESULTS
Twenty-two eyes were randomized to treatment, and 22 eyes served as controls. Five patients failed to complete the study; three patients discontinued study drops on their own (one case in the study group and two cases in the control group), one patient (study group) failed to come back for follow up after 1 month, and one patient (control group) underwent a tube shunt surgery instead of trabeculectomy as planned. Twenty patients in the control group and 19 patients in the treatment group completed the study. The patients were followed for a period of 623 months (median, 10 months).

2.52 0.51 23 6 13 17 2 13 1 5

2.80 0.69 24 9 11 20 0 12 0 8

Patient population characteristics

Patient demographic and clinical characteristics are summarized in Table 1. There was no signicant difference between the groups regarding age, gender, race, type of glaucoma, type of surgery, type of conjunctival ap, baseline glaucoma medication, type of antimetabolite and prior eye surgery.

Visual acuity
There was no signicant difference in the preoperative (P = 0.65) and postoperative last visit (P = 0.50) LogMAR best corrected visual acuity between the groups.

BCVA, best corrected visual acuity; IOP, intraocular pressure; NVG, neovascular glaucoma; PACG, primary angle-closure glaucoma; PEXG, pseudoexfoliative glaucoma; POAG, primary openangle glaucoma; SD, standard deviation.

(P = 0.837) (Table 2). The change in IOP was not signicant between the two groups (P = 0.36).

Intraocular pressure
The mean baseline IOP in the treatment and control groups was 23.8 12.6 and 25.9 10.6 mmHg, respectively (P = 0.513). This value at postoperative month 6 was 14.88 6.2 and 14.62 5.46 mmHg in the study group and control group, respectively

Schirmers tear test 1

The mean difference in STT1 6 months after the surgery was -2.13 7.25 in the control group (P = 0.22) and -2.90 9.64 in the treatment group (P = 0.20). There was no statistically signicant difference

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Table 2. Intraocular pressure pre- and postoperatively in the treatment and control groups IOP Treatment Baseline Month 6 23.8 14.88 12.6 6.2 Group Control 25.9 14.62 10.6 5.46 0.513 0.837 P-value

Fakhraie et al. 0.125) SPK between the two groups, but this value was statistically different between the two groups at postoperative week 1 (P = 0.031) and month 1 (P = 0.047).

Conjunctival hyperaemia
There was no statistically signicant difference in the level of conjunctival hyperaemia between the two groups at baseline (P = 0.94), 1 (P = 0.81) and 6 months following surgery (P = 0.83).

IOP, intraocular pressure.

20 18 16 Paper wetting (mm) 14 12 10 8 6 4 2 0 Control Treatment Baseline Month 1 Month 6

Bleb appearance
At week 1, there was a trend toward less conjunctival haemorrhage and bleb vascularity with topical cyclosporine than with vehicle. Mean haemorrhage scores were 0.42 with CsA, compared with 0.84 with vehicle (P = 0.07). The mean bleb vascularity scores were 1.1 with CsA, compared with 1.4 with vehicle (P = 0.61). There was no statistically signicant difference in bleb morphology scales between the two groups at month 6 postoperative visit.

Glaucoma medication
The mean number of glaucoma medication at baseline was 2.8 0.69 in the control group and 2.52 0.51 in the treatment group (P = 0.172). This value at the last visit was 1.1 0.64 in the control group and 0.94 0.7 in the treatment group (P = 0.483). The number of cases without using glaucoma medication at last visit was 12 (63%) in the study group and 9 (45%) in the control group (P = 0.256).

Figure 2. Baseline and postoperative month 6 amounts of Schirmers test in the treatment and control group.

in mean values of STT1 between the two groups at baseline (P = 0.843), 1 month after surgery (P = 0.64) and 6 months after surgery (P = 0.91). Figure 2 shows the mean values of STT1 before and after surgery.

Ocular surface disease index

Baseline OSDI scores for the control and treatment groups were 31 22 and 28 23, respectively (P = 0.663). The OSDI score 6 months following surgery showed a statistically signicant difference between the two groups (P = 0.021) (Table 3). The mean decrease in OSDI was 14 17 in the treatment group (P = 0.002) and 8 15 (P = 0.024) in the control group. Lower OSDI score means less severity of dry eye symptoms and less impact on vision-related functions. Topical CsA provided a statistically signicant reduction in patient pain following trabeculectomy. In the CsA-treated eyes, the main pain score (one component of the OSDI questionnaire) was 0.15 at month 6 (P = 0.016), compared with 0.40 with vehicle (P = 0.29).

Success rate
Success at last visit was achieved in 17 (85%) cases in the treatment group and in 15 (75%) cases in the control group (P = 0.407).

DISCUSSION
Chronic topical therapy with low concentration CsA was used to evaluate effect on the outcome of glaucoma surgery. In the present study, topical CsA 0.05% drops following trabeculectomy did not appear to change the outcomes in terms of further IOP reduction, success rate or appearance of the blebs. Turacli et al. showed a benecial effect of intraoperative applied CsA 2% during ltration surgery and attributed this to the inhibitory effect of CsA on T-helper cells, and by extension, to the cytokines and growth factors produced by these cells.3 We hypothesized that topical application of CsA 0.05% drops

Supercial punctatae keratitis

There was no statistically signicant difference in the baseline (P = 0.763) and postoperative day 1 (P =

2009 The Authors Journal compilation 2009 Royal Australian and New Zealand College of Ophthalmologists

Cyclosporine following trabeculectomy

Table 3. Ocular surface disease index pre- and postoperatively OSDI Treatment group Control group P-value Baseline (mean SD) 27.91 23.17 30.96 22.02 0.663 Month 1 (mean SD) 27.79 28.64 29.78 21.19 0.483

847

Month 6 (mean SD) 13.84 11.59 22.81 22.84 0.021

OSDI, ocular surface disease index; SD, standard deviation.

postoperatively might similarly affect the brosis at the ltration site comparable to intraoperative application. In our study population, in which use of CsA was limited to postoperative application, we did not note a benecial effect on IOP. This could be related to low concentration of CsA (0.05%) and inadequate penetration of CsA through the conjunctiva and/or the cornea. However, postoperative topical administration of a stronger concentration of CsA (2%) has previously been studied; using a rabbit eye model.16 This study found that topical CsA (2%) did not improve bleb function and in fact signicantly lessened the benecial effects of intraoperative MMC in lowering IOP.16 Therefore, strengthening the concentration of CsA would not necessarily improve IOP results postoperatively. We also evaluated the effect of CsA 0.05% on ocular surface inammation. Ocular surface inammation following trabeculectomy can enhance bleb brosis, hence decrease bleb function and increase failure rate. One of the indices for evaluation of ocular surface inammation is conjunctival hyperaemia and inammation. Our ndings showed that in this concentration of CsA, there was not any statistical signicance difference in conjunctival hyperaemia and inammation between the two groups at postoperative week 1, months 1 and 6. We also investigated whether the use of CsA improved the symptomatic postoperative course following trabeculectomy. Primary open-angle glaucoma itself is associated with an impaired basal tear turnover.17 In addition, ocular irritation is a common complaint of glaucoma patients on eye drops.18,19 This irritation is not limited to medication use alone as has been shown by the Collaborative Initial Glaucoma Treatment Study. In this study 607 patients were followed for over 5 years, and it was found that patients subjectively noted signicantly more eye irritation after trabeculectomy compared with longterm medication use.20,21 Although these results are subjective, it has objectively been shown that frequent use of eye medications actually alters the conjunctival anatomy.22 Studies have found that in patients chronically treated with glaucoma eye drops, there is a signicant decrease in goblet cell density2224 and a signicant decrease in Schirmers test leading one study to conclude that patients on

chronic 0.5% timolol could be considered to be in a dry-eye state.23 Patients undergoing trabeculectomy may therefore be predisposed to developing ocular irritation after the procedure, and the results of this study may be useful in improving patient satisfaction and comfort. It has been reported that CsA is associated with a decrease in conjunctival inammation, an increase in conjunctival goblet cells and improvement of Meibomian gland dysfunction.6 Hence, the drug has promise for treating both decient tear production and evaporative tear loss.6 Although CsA is already used for the treatment of dry eye syndromes, this study suggests that there may be a role for CsA post trabeculectomy, specically to alleviate symptoms of ocular irritation. Our results have shown that patients on CsA 0.05% experienced less pain and discomfort and tended to have less conjunctival hyperaemia compared with those on articial tears, following trabeculectomy. Considering the lack of any difference in tear production (STT1) between the two groups, this may be as a result of the modulatory effect of topical CsA on conjunctival goblet cells and Meibomian gland secretion and change in tear components. However, considering the cost of topical cyclosporine 0.05% and patient inconvenience, patients with previous ocular surface disease and those patients likely to experience bleb irritation seem to be the appropriate candidates. Patients receiving CsA post glaucoma surgery for 6 months had signicantly less postoperative ocular irritation and discomfort than the control group, suggesting a possible benecial role for topical postoperative CsA in decreasing ocular surface symptoms following glaucoma ltering surgery in patients with pre-existing ocular surface disease. Topical cyclosporine had no benecial effect on bleb function and IOP control.

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2009 The Authors Journal compilation 2009 Royal Australian and New Zealand College of Ophthalmologists