Dr. Sunita Pandey, S20316, Dr. Pramod Kumar Sharma, Dr. Kanhei Charan Tudu, Dr. Sharmistha Behera
Abstract
Purpose: To study safety & efficacy of 0.1% Cyclosporine drops in preventing bleb failure post Trabeculectomy. Materials and Methods: randomized prospective study involving 42 patients of POAG requiring trabeculectomy. Study group (n=22) received 0.1% topical cyclosporine twice daily and control group (n=20) received artificial tears. Follow up period 6 months with monthly evaluation. Outcome measures were functioning bleb and conjunctival inflammation. Results: functioning bleb at 6 month follow up-70% (15) in study and 40% (8) in control. Study group had statistically significant decrease in ocular inflammation with good functioning filtration bleb. Conclusion: Topical Cyclosporine 0.1% is safe & effective in preventing bleb failure in Trabeculectomy.
Introduction
The most common cause of glaucoma surgery failure is sub-conjunctival fibrosis in the bleb. Rapid wound-healing response can present in one of two ways:
- Sub-conjunctival fibrosis leads to lack of filtration and a flat bleb with subsequent increases in IOP. This can occur at any stage after the operation and is the most common cause for failure after trabeculectomy, both in the early and late postoperative periods. The incidence of failure from sub-conjunctival fibrosis is approximately 20% in the early period and 30% to 50% in the late postoperative period.
- Sub-Tenon’s encapsulation of blebs presents as raised, often angry-looking blebs with elevated IOP. This usually occurs in the first 1 to 6 months after surgery and is seen in 10% to 20% of patients after trabeculectomy.
In an attempt to control the fibrotic response, anti-inflammatory agents such as steroids, and anti-metabolites such as Mitomycin-C (MMC) and 5-fluorouracil (5-FU), have been used. They have increased the success rate of trabeculectomy to 80% to 85% at 1 year. Five-year success rates are still around 50% to 60% despite the use of anti-metabolites. Thus, increasing IOP with failing blebs is an issue after any kind of glaucoma surgery. Herein we present our technique in prevention of bleb failure after trabeculectomy using topical 0.1% Cyclosporine-A (CsA) drops post trabeculectomy.
CsA inhibits T cells proliferation and prevents the release of pro-inflammatory cytokines by blocking the activity of calcineurin, a ubiquitous enzyme found in cell cytoplasm that is implicated in the control of replication of the genes for IL-2 and other pro-inflammatory cytokines.
Several basic and clinical trials have demonstrated that CsA in oleic emulsion decreases the signs and the symptoms of ocular allergic disease [1,2] .Topical CsA treatment also has an advantage in that it lacks the serious adverse ocular effects[3].
Nonetheless, currently available systems using oils to deliver CsA are poorly tolerated and provide low bioavailability of the drug. Patients treated using these formulations of CsA have reported moderate to intense stinging, tearing, redness and swelling of lids after drop instillation [4]. CsA is a lipophilic molecule that it must be regularly dissolved in an alcohol-oil base, which causes the ocular irritation mentioned above [5,6]. However, these difficulties may be overcome through formulations aimed at improving the water solubility of CsA, facilitating tissue drug penetration, or by using penetration colloidal carriers (micelles) [7].
In the present study, we evaluated the safety and efficacy of 0.1% concentrations of a topical aqueous solution CsA in post trabeculectomy POAG patients.. This CsA-carrier association creates a mono-disperse, stable, micelle solution, which is free of benzalkonium chloride [8].
Materials and Methods:
This was a comparative and prospective clinical study. It was reviewed and approved by the Ethics Committee of our center. The study was conducted in accordance with the ethical principles of the Declaration of Helsinki.
All patients underwent a complete preoperative ophthalmic examination, including best-corrected visual acuity (BCVA), Goldmann applanation tonometry, slit-lamp examination, ophthalmoscopy, gonioscopy, and visual field examination (Humphrey Perimeter, SITA Standard 30-2 program) to make the diagnosis of POAG. The primary indicators used to measure outcomes were IOP, BCVA, the number of anti-glaucoma medications used, complications, bleb appearance.
The POAG patients on maximal medication with uncontrolled IOP were organized randomly in two groups who underwent trabeculectomy. Study group (n=22) received the CsA 0.1% aqueous ophthalmic solution (nanotears, sunways), in a dosage of one drop every 12 hours in the operated eye from 1st postoperative day (8:00 h and 20:00 h ±1 hour) during the 6 months of the study. Control group (n=20) received the artificial tear drops within the same duration as in group A along with topical steroids , during the 6 months of the study.
On each follow-up visit, visual acuity, biomicroscopy, and IOP were obtained. Fundoscopy under pupillary dilation was performed only on weeks 12 and 24.
Complete success was defined as maintenance of IOP≥6 mm Hg and≤21 mm Hg, in absence of further surgery or use of anti-glaucoma medication. Qualified success refers to meeting the above criteria with or without use of anti-glaucoma medications. The need for further anti-glaucoma medication, repeat trabeculectomy or glaucoma drainage device would constitute surgical failure.
The qualified success rates at month 6 for POAG and PACG were 23.8% and 29.9% respectively, 32.2% and 29.2% at month 12, and 34.7% and 29.6% at month 24. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4539629/
Statistical Analysis
Basic statistical analyses were performed using IBM SPSS statistic version 21 (IBM corp, Armonk, NY, USA). Mean with standard deviation (SD) were calculated for continuous variables and frequency with percentage were tabulated for categorical variables. Student’s t-test was used for continuous variables and χ2 test for categorical variables.
A p value < 0.05 was considered statistically significant]
Results
Demographic profile
| No. of POAG eyes | 42 (n1= 22) (n2=20) |
| Gender (no., %) | |
| Women | 25 (59.5%) |
| Men | 17 (40.4%) |
| Mean age (yrs) | |
| Women | 56 |
| Men | 54 |
Mean preoperative IOP = 26.1±8.4 mmHg
Mean postoperative IOP in mmHg
| Follow up visits | Study group (n1) | Control group (n2) |
| D1 | 12.1±9.5 | 12.0±9.4 |
| WK1 | 13.2±5.7 | 13.4±5.6 |
| WK4 | 15.0±4.3 | 16.0±5.7 |
| WK12 | 15.3±5.7 | 21.0±4.8 |
| WK24 | 15.1±3.6 | 23.0±5.8 |
Reduction in IOP postoperatively from baseline 26.1±8.4 mmHg to 15.1±3.6 mmHg is significant (p< 0.05) in study group whereas in control it reduced to 23.0±5.8 (p>0.05) from baseline at 6th month of follow up.
| Follow up visits | Absolute success | Qualified success | Failure |
| Study Group | |||
| D1 | 22 | 22 | 0 |
| WK1 | 22 | 22 | 0 |
| WK4 | 21 | 21 | 1 |
| WK12 | 16 | 17 | 5 |
| WK24 | 13 (59%) | 15 (68.2%) | 7 (31.8%) |
| Control Group | |||
| D1 | 20 | 20 | 0 |
| WK1 | 20 | 20 | 0 |
| WK4 | 20 | 20 | 0 |
| WK12 | 12 | 13 | 7 |
| WK24 | 6 (30%) | 8 (40%) | 12 (60%) |
At 24 weeks of follow up visit, about 68.2% of patients achieved qualified success and 59 % absolute success (p=0.012) in study group whereas in control, 40% achieved qualified success and 30% absolute success (p=0.26).
Bleb Appearance at Week 24 on Slit Lamp examination
| Bleb morphology | Study group | Control group |
| Diffuse filtering | 9 | 5 |
| Cystic | 6 | 3 |
| Encapsulated | 3 | 7 |
| Flattened | 4 | 5 |
On an average all the patients were on maximal anti-glaucoma medications with uncontrolled IOP
No serious adverse effects were reported in either of the groups during the follow-up period. In the case report forms we did not find reports of corneal involvement, nor before starting neither during the study period.
No local or systemic infection, bleb rupture, Aqueous leakage, corneal lesions, blindness and bleeding were encountered in any cases.
Discussion
The completion of trabeculectomy surgery is the beginning of a process that takes several months to complete. During this period, alterations in bleb morphology and aqueous outflow due to the scarring response could influence the long‐term success of the surgery. There are several indicators that point to a failure of the bleb including excessive conjunctival injection and corkscrewing of vessels, flattening of the bleb, encysting of the bleb and increasing IOP. Frequent monitoring, at least weekly for the first month (and more often when required), allows changes in bleb characteristics to be identified early while a window of opportunity exists to modulate these changes. Frequent follow‐up of patients in the postoperative period is therefore an essential part of the postoperative management of trabeculectomies.
Cyclosporine-A (CsA) is commonly used in the treatment of many inflammatory eye diseases as an immunomodulatory and anti-inflammatory agent [9,10]. Unlike other anti-inflammatory agents including corticosteroids, topical CsA improves ocular surface symptoms [11] with minimal adverse effects [12,13,14]. The anti-metabolite property of this agent in GFS have been investigated in some prospective, randomized clinical trials [11,13,14]. Fakhraie et al [11] in their study in glaucomatous patients who underwent GFS and received intra-operative MMC or 5-FU, reported that topical CsA had no effect on postoperative bleb function and IOP. A prospective, randomized clinical trial on anti-metabolite properties of CsA in GFS found positive response and suggested more studies to substantiate its adjuvant role in GFS [13,14]
Considering its broad therapeutic properties including immunomodulatory, anti-inflammatory, immunosuppressive and anti-metabolite activities, and the low incidence of its adverse effects on the eye, we hypothesized the efficacy of 0.1% CsA in preventing bleb failure post trabeculectomy in POAG patients on maximal medications and hence drug related toxicity reduced
This aqueous CsA formulation was also able to improve tolerance and compliance to the treatment.
We believe that the present formulation used in this study could increase bioavailability and allow higher effective concentrations of the drug in the ocular tissue without having to raise the raw concentration. This work is not the first to show the efficacy of CsA in treating ocular disease. In fact, similar findings regarding efficacy have been reported with CsA eye drops but with different concentrations and vehicles [15,16,6,17,18,19,20,21]
We did not observe any complication in the administration of CsA in our patients during the study period. However, the topical CsA 0.1% aqueous solution was efficacious in achieving improvement of the signs and symptoms of ocular inflammation. Additionally, the fact that CsA has been formulated in an aqueous solution increases the bioavailability of the drug in the cornea and conjunctiva [8].
Conclusion
In conclusion, topical application of a 0.1% CsA aqueous solution has been shown to be safe, effective and well tolerated in prevention of bleb failure after trabeculectomy in POAG patients.
Topical 0.1% CsA successfully inhibited fibrous tissue proliferation. Though success rate seen in trabeculectomy with topical MMC is more but at the cost of vision threatening complications, so we recommend a more prolonged study with adequate sample size and longer duration of follow up
Abbreviations
CsA- Cyclosporine A
IOP – intraocular pressure
GFS- Glaucoma filtration surgery
MMC-Mitomycin- C
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