Incidence and risk factors for postkeratoplasty glaucoma in tertiary care center, India.

BACKGROUND: Glaucoma is the leading cause of blindness after penetrating keratoplasty (PK) and its early diagnosis and management is mandatory to salvage the graft. AIMS: This study aimed to evaluate the incidence and risk factors for post penetrating keratoplasty glaucoma (PKG).
METHODS: Data of 155 eyes of 155 patients were reviewed retrospectively who underwent PK from March 2013 to February 2016. Data were analyzed from recipient records for recipient age, sex, indications, type of PK, lens status, recipient graft size or any additional procedure. Detailed ophthalmological examination was recorded for all cases including best corrected visual acuity (BCVA), slit lamp examination, intraocular pressure (IOP) by applanation tonometry or tonopen, central corneal thickness (CCT) and gonioscopy. IOP measurement records were reviewed at each visit of one week, two weeks,one, three and six months and if IOP was elevated (>22 mmHg) medical management was initiated. Uncontrolled IOP with antiglaucoma medication (AGM) required surgical management.
RESULTS: Overall incidence of raised IOP after PK was 32.25%. Increase in IOP post PK was reported mainly in 32 (64%) among age group >40 years. Raised IOP showed significant association with age group, indications of PK, recipient size and CCT (P value 0.00, 0.01, 0.00, 0.00) respectively. Two weeks after PK 46 (29.67%) patients reported an increase in IOP ,47(30.32 %) after 1 months, 33 (21.29%) at 3 months and 30 (19.35%) at 6 months. In 11 (39.28%) cases cataract was major long term complication seen in PKG cases. 35 (70%) cases of PKG were treated medically and 15 (30%) patients required surgical treatment.
CONCLUSION: Subjects with age group >40 years, corneal opacity, increased recepient size and increased CCT are risk factors for PKG. IOP monitoring in early post operative period especially one month after PK is mandatory to avoid graft failure due to PKG which is difficult to diagnose otherwise.

Introduction

Allograft rejection and severe astigmatism are well-known complications of penetrating keratoplasty (PK), but postkeratoplasty glaucoma (PKG) is one of the most common causes for irreversible visual loss and the second leading cause for graft failure due to significant endothelial cell loss, especially in patients who have already low endothelial reserve.[1] The amount of cell loss appears to correlate with the duration of the increased intraocular pressure (IOP). The association of glaucoma after PK was first described by Irvine and Kaufman.[2] They also showed a bipeaked rise in IOP, the first in the immediate postoperative period with IOP normalization later and the second in the last postoperative period (weeks to months). Early diagnosis of PKG is mandatory to preserve optimal graft clarity and optic nerve head function.[3] PKG is defined as an elevated IOP >21 mmHg within 1 month of PK with or without associated visual field loss or optic nerve head changes. Tonometry is difficult in these cases because of thick or astigmatic corneal graft. Assessment of the optic nerve and visual field before or after surgery is nearly impossible because of preoperative hazy media and postoperative high corneal astigmatism which makes the diagnosis difficult.[4]

The incidence of PKG differs significantly from 0%–12% to 75%.[5] The incidence of post-PK increase in IOP has been reported to be within the range between 9% and 35%.[67] This incidence was associated with several risk factors. These include the indication for keratoplasty, the status of the lens, additional procedures at the time of keratoplasty, and preexisting glaucoma.[8] The present study was conducted to know about the incidence of PKG and factors associated with it after PK at tertiary care center, India.

Methods

The observational study was approved by the Research and Ethical Committee of the institute and was in accordance with the tenets set forth in the Declaration of Helsinki. Data were reviewed retrospectively for the patients who had undergone PK from March 2013 to February 2016.

Inclusion criteria

The patients who underwent PK with good postoperative graft clarity but developed raised IOP which could not be controlled or noncompliant with topical drugs or difficulty in follow-up and preexisting glaucoma which worsened and could not be controlled with topical drugs were included in the study.

Exclusion criteria

The patients with a history of glaucoma surgery or uveitis previously, one-eyed patients, very elderly patients, pregnant women, patients with thrombocytopenia, coagulation disorders, immunocompromised status, herpetic keratitis, or any history of hypersensitivity were excluded from the study.

Corneal retrieval, surgical technique, and postoperative care were of consistent regimens. Donor tissue was distributed by the eye bank according to the Eye Bank Association of America Medical Standards or rejected because of medical, social, structural or serological contraindications adversely affecting the donor cornea.[9] Corneoscleral rim excision was done for all eye donations and donor tissue was collected in McCarey-Kaufman medium with all aseptic precautions. Tissue grading was done according to grading chart by National Eye Bank as Grade A, B+, B, B−, and C[10] and donor tissues graded A, B+, B, and B − were used for PK purpose.

The preoperative ophthalmological examination was reviewed for the recipients, which consisted of the measurement of uncorrected visual acuity, manifest refraction, best-corrected visual acuity (BCVA) with fully corrective glasses or rigid gas permeable contact lenses (if possible), slit-lamp biomicroscopy, dilated fundus examination, or B-scan if fundus was not visible.

Surgical procedure

Preoperative injection of mannitol was given in all cases. PKs were done under peribulbar anesthesia and general anesthesia in certain indications such as perforated corneal ulcers, pediatric age group, and uncooperative patients. During the operative procedure, donor graft 0.5-mm larger than recipient's size was obtained by trephination of corneoscleral button with endothelial side up and viscoelastic over teflon block. After proper anesthesia, recipient bed was prepared using 0.5 mm less size trephine than the donor. The graft was applied after putting viscoelastic substance over iris surface and four cardinal sutures, primary sutures at 12, 3, 6, and 9 o'clock position and the rest of the suturing were done in interrupted or continuous fashion with 10-0 nylon. Depending on the indications, vascularity, and infection, both interrupted and continuous suturing were done. Histopathological examination was done for the recipient button and donor corneoscleral rim. Routine postoperative medication consisted of topical prednisolone 1% combined with preservative-free topical antibiotic, artificial tears, cycloplegics, and antiglaucoma, if required, followed by tapering topical steroids. Routine follow-up schedule was weekly for the 1st month, biweekly for the 2nd month, monthly for 3 months, and 3 monthly afterward. To exclude the surgical bias, all patients included in the study were operated by one surgeon.

Data were analyzed from recipient records for recipient age, sex, indications, type of PK, presence of glaucoma before PK, medications used, lens status, graft clarity, preoperative IOP, combined cataract surgery, recipient graft size, intraocular lens (IOL) explantation, iridoplasty, goniosynechiolysis, and anterior vitrectomy. Detailed ophthalmological examination records were analyzed including BCVA, slit-lamp examination, IOP by applanation tonometry or tonopen (whatever possible) at least three consecutive readings, central corneal thickness (CCT), gonioscopy, and anterior segment optical coherence tomography. IOP readings were reviewed at each visit of 1 week, 2 weeks, 1 month, 3 months, and 6 months. Medical management was initiated if IOP was elevated (>22 mmHg) using topical timolol maleate (0.5%), brimonidine purite (0.15%), latanoprost (0.005%), and brinzolamide (2%), and oral carbonic anhydrase inhibitors were added, if needed. However, if IOP remained high despite antiglaucoma medication (AGM) with or without graft edema or failure, then surgical management was planned as trabeculectomy with or without mitomycin C [Figure 1a and b]. Early and long-term complications were noted in all cases of PKG till average of 6 months.

Figure 1

(a) Severe graft edema with postkeratoplasty glaucoma (b) Same graft 2 weeks posttrabeculectomy with mitomycin C

Statistical analysis

Data were initially entered into a Microsoft Excel spreadsheet and then transferred to SPSS software (Statistical Package for the Social Sciences, version 22, SPSS Inc., Chicago, IL, USA). The quantitative factors such as age, recipient graft size, CCT, graft clarity, and additional procedures and qualitative factors such as gender, laterality, indications of PK, and lens status were included in the data. Data of continuous measurements were expressed in terms of means ± standard deviations and results on categorical measurements were presented in number or percentage.

Independent risk factors for PKG were identified using univariate and multivariate analyses. The Chi-square analyses had been carried out for categorical data. Variables found to be significant in the univariate analysis were included in a multivariable binary logistic regression analysis with the presence of PKG as the dependent variable. P < 0.05 was considered statistically significant.

Results

Records of total 155 eyes of 155 patients were reviewed and studied. The analysis of demographic characteristics showed that majority, i.e., 110 (70.96%) patients were >40 years of age with a mean of 49.58 ± 18.73 years and range from 10 to 83 years. Increased IOP was reported in 64% of patients with age group >40 years. In this study, the number of men (110 of 155, 70.96%) was higher than women (45 of 155, 29.03%). The left eye was operated in 88 (56.77%) of study participants. In the present study, 50 of 155 consecutive eyes who underwent PK developed high IOP, giving an overall incidence of 32.25% with a follow-up of 6 months. Indications of PK included mainly corneal opacity 56 (36.12%) followed by graft failure 32 (20.64%). Status of the lens was phakic in 116 (74.83%) of patients. Majority, i.e., 83 (53.54%) of patients had BCVA between 20/60 and 20/200. Fifty (32.25%) patients showed increased IOP post-PK in the present study out of which three patients had preexisting glaucoma and these patients eventually developed glaucomatous optic atrophy. Three patients were diagnosed as steroid responders who needed surgical intervention, but one of them developed glaucomatous optic atrophy [Table 1]. Meantime of diagnosis of raised IOP was 1.92 months. Univariate analysis was performed to identify individual risk factors for PKG. In this analysis, age, sex, laterality, lens status, graft clarity, and additional procedures were not found to be significant risk factors for PKG (P = 0.19, 0.25, 0.22, 0.86, 0.27, and 0.73). In contrast, the indication for PK, size of recipient graft, and CCT were found to be significant risk factors affecting PKG (P = 0.01, 0.00, 0.00) [Table 2]. Risk factors identified by univariate analysis were subjected to multivariate logistic regression analysis, and in addition to the previous significant factors, age was found to be associated with PKG (odds ratio [OR], 0.21; 95% confidence interval, 0.07–0.65; P = 0.001) [Table 3].

Table 1

Baseline characteristics of patients with post keratoplasty glaucoma

Table 2

Association between development of glaucoma postpenetrating keratoplasty and its various risk factors

Table 3

Multivariate logistic regression analysis for the assessment of various risk factors of postkeratoplasty glaucoma

Significant association was found between the age group and an increase in IOP (P = 0.00). PKG showed no association with gender and BCVA [Table 3]. During the follow-up period, no case showed increased IOP at the end of 1 week. After 2 weeks, 46 (29.67%) patients showed increased IOP, 47 (30.32%) after 1 months, 33 (21.29%) at 3 months, and 30 (19.35%) at 6 months. Cataract was the major long-term complication seen in 11 (39.28%) patients, followed by iritis (25%) in the present study [Figure 2]. Of 50 patients with raised IOP after PK, 35 (70%) were given medical therapy and 15 (30%) patient required surgical treatment [Table 4].

Figure 2

Pie chart depicting the long-term complications after postkeratoplasty glaucoma

Table 4

Follow up and management of postkeratoplasty glaucoma

Discussion

PK is considered to be a successful surgical procedure, but postoperative visual rehabilitation is prolonged due to a slow healing process. Glaucoma is a serious complication after PK. The outcome of PK depends on indications, operative techniques, and postoperative care.[11]

In the current study group, mean age was 49.58 ± 18.73 years, and 70.96% of the patients were 40 years of age of which 70.96% were male, and 29.03% were female. In the present study, increase in IOP was reported mainly in age group >40 years which is in concordance with the observations of Dodia et al.[12] that age above 55 years was major risk factors for the postoperative increase in IOP. Karadag et al. reviewed 729 patients with the mean age of 40.9 6 ± 20.4 years of which 61.9% were male and 38.1% were female.[13]

As concluded by Dodia et al. and Sharma et al. that male patients with age >40 years, having opaque grafts as an indication were found to be at higher risk of developing PKG which is in concordance with the present study.[1214] Sharma et al. validated an equation to quantify the cumulative effect of various risk factors of PKG to the tune of 88% accuracy in prospective study which we could not use as this study was retrospective in nature.[14]

In the present study, overall incidence of PKG was 32.25% with a follow-up of 6 months. Simmons et al. also reported an incidence of 34% of PKG within a mean time interval of follow-up of 24 weeks which is consistent with the present study.[15]

Karesh and Nirankari reported the incidence of PKG varying from 9% to 31% in the early postoperative period and from 18% to 35% in the late postoperative period.[16] In a recently reported series, the incidence of PKG was found to be 18%. In another study by Sekhar et al., overall incidence of 27.4% of high IOP after PK was reported.[17] Karadag et al. found the incidence of PKG as 16.6% in the late postoperative period.[13] In the current study, the mean period of time between PK and the first occurrence of glaucoma was 1.92 months similar to the observations of Dodia et al., who reported peak rise in IOP following 2 months after PK.[12]

The risk of PKG is correlated with the indications of PK significantly. In the present study, it was observed that cases with graft failure were at higher risk (30%) of developing PKG whereas anterior staphyloma (0%) and corneal dystrophy (2%) were at lower risk as reported by Hemanth Raj et al.[18] Sekhar et al. observed that in conditions such as aphakic bullous keratopathy, pseudophakic bullous keratopathy, and vascularized corneal scar, the incidence of PKG was high (30%–42%), while in keratoconus and corneal dystrophies, it was low (6 and 16%, respectively).[17] Karadag et al. recently reported the higher risk of PKG in bullous keratopathy (RR = 2.59), graft rejection (RR = 2.61), traumatic scar (2.66) and lower risk in patients who underwent PK for keratoconus (RR = 0.15), and corneal dystrophy (RR = 0.42).[13]

In the present study, preoperative lens status showed correlation with PKG. One hundred and sixteen (74%) phakic patients were at high risk of developing raised IOP following PK compared to 37 (23.87%) pseudophakic patients though it was not statistically significant (P = 0.86). This result was consistent with the observations of Gupta and Gupta who reported the highest incidence of PKG in phakic eyes, which may be due to development of posterior synechiae and intumescent cataract, which was main complication in the present series.[19] Some studies found that aphakic and pseudophakic eyes had a greater tendency for PKG as compared to phakic eyes.[8] Karadag et al. found a higher incidence of PKG in pseudophakic and aphakic eyes compared with the phakics (P = 0.001) unlike the present study.[13] Because of only two aphakic eyes in this study, no significant relation was observed.

Simmons et al. showed that postoperative elevated IOP was significantly more likely in aphakic eyes than in phakic or pseudophakic eyes, with chronic IOP rise in 46% of aphakic eyes.[15] Polack and Goldberg et al. concluded that preoperative glaucoma accounts for the high incidence of elevated IOP in aphakic eyes postoperatively.[2021] As larger disparity of graft size in aphakia is recommended, so large size graft or aphakia per se is an independent risk factor for postkeratoplasty IOP elevation is controvertial.

Preexisting glaucoma and additional procedures combined with PK were the leading risk factors for ocular hypertension, as reported by Oruçoglu et al.[22] Similarly, in the present study, goniosynechiolysis was major risk factor for PKG. In the current study, recipient size >8 mm was at higher risk 41 (82%) with OR 6.66 (2.45–18.04) for raised IOP which was consistent with the reports of Hemanth Raj et al.[18] Large-sized grafts >8 mm showed more chance of PKG as large button may affect the iridocorneal angle. Panda et al. noted an incidence of PKG of 37% in eyes with 10-mm grafts as compared to 14% in eyes with 6–7.5-mm grafts.[23] Steroids play an important role in the pathogenesis of glaucoma. Postoperative use of steroids controls inflammation and reduces the likelihood of peripheral anterior synechia, thus reducing the risk of IOP elevation. In contrast, topical steroids may induce steroid-induced ocular hypertension. Most of our patients were under the treatment of steroids during the period of elevated IOP. When high IOP was observed, steroids were tapered down, stopped, or switched to the weaker steroids. As almost all of our patients were maintained on topical corticosteroids postoperatively, it was difficult to assess the effect of steroids on the incidence of PKG.

Medical management (topical drops or systemic) is still the first line of treatment in cases of glaucoma following PK.[24] In the current series, majority, i.e., 35 (70%) of the patients were managed medically. Surgical intervention was required only when IOP was not controlled by maximum tolerant medical therapy. Surgical intervention was required in 15 (30%) of patients as compared to the study by Sekhar et al. where 73% of patients were managed medically and 27% of patients required surgical intervention.[17] Trabeculectomy was the procedure of choice in this series. Cyclocryotherapy was done in two patients and those grafts failed eventually.

Lin et al. studied 28 patients with PKG who failed to respond to AGMs and routine filtering procedures and were treated with cyclocryotherapy. The results showed controlled IOP in 89% of the eyes.[25]

Limitations

The present study was a small-scale study with few participants in few indications due to which significant statistical analysis was not possible. The post-PK follow-up till 6 months was less still long-term follow-up was required to monitor IOP. We did not evaluate the donor-related factors such as death-to-preservation time and death-to-utilization time which affect the graft thickness and eventually influence IOP. Suturing technique of the graft was not taken into account which can affect post-PK IOP. A donor button 0.5-mm larger than the host bed has been shown to be associated with a lower incidence of postoperative glaucoma, but in our study, this oversizing was not evaluated as we used donor button oversized by 0.5 mm in all cases.

Conclusion

The incidence of PKG was 32.25% and was reported mainly in age group >40 years. PKG shows a significant association with preoperative diagnosis of corneal opacity, size of recipient graft, and CCT. Knowledge of these risk factors may help to limit the occurrence of glaucoma and to increase the chances of success of PK. IOP monitoring should be started in the early postoperative period of PK to avoid its deleterious effect on the health of graft. Any patient with a history of preexisting glaucoma should be carefully evaluated before and after PK. Additional procedures such as goniosynechiolysis during PK increase the risk of PKG. Surgeons should probably consider the risk associated with combined procedures. The introduction of lamellar techniques for corneal transplantation may further decrease the incidence of post-PK ocular hypertension.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.