European Journal of Cardiovascular Medicine

Bullous keratopathy can be caused by various diseases and surgeries, including Fuchs corneal endothelial dystrophy, iridocorneal endothelial dystrophy, cataract surgery, and glaucoma surgery. ^[1] Trabeculectomy is one of these possible causes for bullous keratopathy. Both intra- operative insult to the corneal endothelium by surgical manoeuvres and anti-metabolites, as well as intra- and post- operative flat anterior chamber (leading to iris–cornea touching) may induce corneal endothelial dysfunction after trabeculectomy. ^[2]

In Japan, glaucoma surgery (including trabeculectomy) was the third most common cause of bullous keratopathy (5.3%) following cataract surgery (44.4%) and laser iridotomy (23.4%). ^[3] In eyes with bullous keratopathy having previously undergone trabeculectomy, the results of corneal transplantation may be affected by pre-existing glaucoma conditions and the presence of filtrating blebs. ^[4] Alternatively, corneal transplantation may affect the control of intraocular pressure (IOP). ^[5] In this regard, the results of corneal transplantation in eyes with bullous keratopathy having previously trabeculectomy are of great clinical interest. ^[6]

Intraocular lens implantation is recognised as a major advance in the field of ophthalmic surgery in recent years. The high success rate and the safety of this visual rehabilitative procedure has made it the most popular method for correction of aphakia. ^[7] This proliferation has also lead to greater incidence of sight-threatening complications, with pseudophakic bullous keratopathy (PBK) being a leading cause. Though the exact incidence of this condition is not well established due to obvious reasons, Stark et^[8] all have reported a rate of corneal decompensation at one year to be 0.06% for posterior chamber (PC) IOLs, 1.2% for anterior chamber (AC) IOLs, and 1.5% for iris-fixated (IF) lenses. Long-term follow-up studies with iris-supported lenses have reported a 15% rate of PBK, whereas it is 0.1 to 0.3% for extracapsular cataract extraction with PC IOL. ^[9]

For the visual rehabilitation of patients with PBK,. penetrating keratoplasty remains the only definitive treatment. The topical issues in penetrating keratoplasty (PK) for PBK are related primarily to the events following removal of the host button and before the donor tissue is sutured in place. However, only a few studies have dealt  with this matter. In this study, we evaluated the results of PK in eyes with bullous keratoplasty having previously trabeculectomy, focusing on the influence of bleb presence on the results. This centres primarily around the management of the existing IOL and the need for anterior segment reconstruction.

This was a prospective interventional study done at department of ophthalmology, Tertiary Care Teaching Hospital. 32 patients with PBK presenting to us were studied.

Informed consent was obtained from all subjects and procedure of the study was described to them. The study was carried out in accordance with the tenets of the Declaration of Helsinki.

Inclusion Criteria

1. Patients with PBK irrespective of type of IOL
2. Failed grafts, previous indication being PBK

Exclusion Criteria

1. Patients with    retinal    detachment,    vitreous haemorrhage, etc as detected on B Scan.
2. Patients with inaccurate projection of

Pre-Operative Evaluation

All the patients were evaluated as follows

1. Detailed history including interval between cataract surgery and development of PBK. Interval between previous grafting and development of graft opacification in eyes with
2. Thorough general and systemic examination
3. Ocular examination: Recording of visual acuity, anterior segment examination on slit lamp of affected eye and other eye especially for endothelial changes by specular reflection. Endothelial cell count was not done due to unavailability of specular microscope. Also type and extent of corneal vascularisation. Fundus examination was done were media clarity permitted. IOP was done by Schiotz’s tonometer because of irregular surface.
4. All patients were subjected to BScan for posterior segment evaluation due corneal opacification.
5. Investigations included were, Complete haemogram, blood sugar profile, ECG and urine examination. All patients had physician fitness before surgery.

Donor Tissue Procurement

1. Donor material was obtained by enucleation within 6 hours of death, with consent of relatives of the deceased.
2. Detailed medical, surgical and ocular history was obtained of the deceased to rule out any contraindication for use of donor material. Cause of death  was  ascertained  in  each 
3. Blood samples were taken for HIV and hepatitis
4. Enucleation was carried out by harvesting whole globe under strict aseptic precautions. Enucleated eyes were immediately packed in glass bottles with cotton packing and were transported in ice packs and then stored at 4oC in refrigerator (moist chamber technique). Donor tissue was used within 48 hours.
5. Donor tissue with intrinsic eye diseases, previous intraocular surgery, ocular hypotony with iridocorneal touch, donor tissue of grade B, donor age above 70 years were not used.
   1. Grading of    donor    tissue:    on    slit    lamp
      1. Grade A:      mild      epithelial      edema
      2. Grade B+: mild epithelial edema and descement’s folds at            periphery
      3. Grade B: marked epithelial edema, stromal edema, descement’s folds till mid periphery
      4. Grade B-: severe epithelial edema, epithelial denudation, marked stromal edema, descement’s folds till                            
      5. Grade C: all of the above changes with more severity but iris and anterior chamber still
      6. Grade D: cornea totally hazy, details of anterior chamber not visible.

7. Also following parameters were noted, age of donor, death enucleation time, enucleation to surgery time and interval between development of PBK and PK.

Surgical Technique

1. Pre operative preparation: All patients received topical gatifloxacin (0.3%) eye drops every 15 minutes for 2 hours prior to Patients with raised IOP were started on oral 250mg, 2 stat or intravenous mannitol 20% in a dose of 1 mg/ kg body weight 30 minutes prior to surgery. Betadine eye drops were instilled 5 minutes prior to surgery.
2. All surgeries were performed under local anaesthesia by peribulbar block. Anaesthetic agent used were, lignocaine 2% with adrenaline (5 ml) along with bupivacaine 0.5% (3 ml) and injection hyaluronidase 75000 IU.
3. All surgeries were performed by single surgeon using standard technique.

Donor tissue was always harvested first, with graft host disparity of 0.5 mm and size of donor graft was 8mm

Donor graft was trephined from eyes and placed on Teflon block.

In eye with vascularisation, cauterization of vessels was done.

Recipient corneal button was trephined with 7.5 mm ensuring proper centration and tilt. Anterior chamber entered with 11 number blade and button was removed with curved corneal scissors. Synechiolysis was done whenever required with viscoelastic agent or iris repositor.

All eyes with posterior chamber IOL were retained after ensuring they are well centred. In 2 eyes IOL repositioning was done. Two eyes with anterior chamber IOL were explanted along with anterior vitrectomy and were left aphakic.

No eyes underwent IOL exchange. Peripheral button hole iridectomy was done in 2 cases with known glaucoma.

Donor graft was sutured to recepient bed with 10-0 nylon suture by placing 4 cardinal sutures at 12, 3, 6 and 9 o clock followed by 12 interrupted sutures. All bites were placed above the level of descement’s membrane of equal length and equidistant from each other. All knots were buried on corneal side.

Intraoperatively all patients received intravenous 1 gm cefotaxim and 8 mg dexamethasone.

1. Post operatively all patients received oral cefotaxim 200 mg BD and combiflam for 5 Oral prednisolone 1 mg / kg body weight was started in all patients and was tapered every 7 days. Topical gatifloxacin (0.3%), prednisolone (1%) and carboxymethyl cellulose (0.5%) were started. Eyes with raised IOP were started on timolol maleate (0.5%) BD or brimonidine (0.2%) TDS or combination of both.

2. All cases were reviewed biweekly for 1 week, weekly for 1 month, fortnightly for 3 months and monthly for 6 months for visual acuity, graft clarity and IOP check.
3. Post operative graft edema was graded as E1 – mild iris details seen, E-2 moderate iris details hazy and E-3 severe iris details unclear.
4. One patient had IOP which was medically uncontrolled, hence treated with diode laser photocoagulation 270o at 6 months.
5. 4 cases had immunological graft rejection during follow up period. These cases were treated with intravenous methylprednisolone pulse therapy, 1 gm/ per day for 3 days followed by oral prednisolone 1 mg/ kg/ body weight in tapering dose. One case recovered while 3 had graft failure and were considered for regrafting.
6. Corneal topography was done in all patients at 6 months. Dioptric power closest to 3mm optical zone at steepest and flat meridian were selected and difference between simulate K value was taken as amount of astigmatism in dioptres

TABLE-1: Age Distribution Of Patients With Bullous Keratopathy

TABLE – 2: Sex Distribution

As per the present study, 26 patients ( 81.25 % ) with bullous keratopathy were above 60 years of age group and 5 patients ( 15.63 % ) with bullous keratopathy were in between 30 to 60 years of age group. As per the present study, 14 males (43.75 %) and 18 females (56.25 %) out of 32 patients were associated with bullous keratopathy.

TABLE – 3: Causes Of Bullous Keratopathy

As per present study, causes of bullous keratopathy in 21 patients ( 65.63 % ) were PBK, in 7 patients ( 21.87 % ) were ABK, in 3 patients ( 9.38 % ) due to previous laser iridotomies and glaucoma surgeries and in 1 patient ( 3.12% ) due to corneal dystrophy out of 32 patients of bullous keratopathy.

With the development of PBK, the number of keratoplasties increased and PBK became the leading indication for PKP in the

United States¹¹. In one report PBK accounted for 2% of keratoplasties in 1976 and had increased to 26% by 1984.¹²

The incidence of PBK was as high as 50% over 5 years in some early European series; that experience delayed IOL development and introduction in the US.^17-21

TABLE – 4: Type Of Cataract Surgery

As per present study, out of 28 patients with bullous keratopathy had history of SICS in 10 patients (35.71 %), ECCE in 9 patients (32.15 %), Phacoemulsification in 3 patients (10.71 %), ICCE in 2 patients (7.14%) and in 4 patients (14.29 %) type of cataract surgery was not known.

TABLE – 5: Status Of Lens In Bullous Keratopathy

As per the present study, out of 32 patients with bullous keratopathy, 11 patients ( 34.38% ) were having ACIOL, 9 patients ( 28.13% ) were having PCIOL and 1 patient ( 3.12% ) was having iris – fixated IOL,total 21 patients were pseudophakic bullous keratopathy. 7 patients (21.87% ) were aphakic and 4 patients ( 12.50% ) were phakic.

TABLE – 6: Visual Acuity And Intraocular Pressure

Table – 6a : Bcva

As per present study, out of 32 patients with bullous keratopathy in 21 patients ( 65.63% ) best corrected visual acuity was worse than 3/60 and in 11 patients ( 34.37% ) BCVA was between 3/60 to 6/60.

TABLE – 6B : INTRAOCULAR PRESSURE

As per present study, IOP was high in 9 patients ( 28.12% ) and normal in 23 patients (71.87%) out of 32 patients with bullous keratopathy preoperatively.

TABLE – 7: Visual Acuity Before And After Pk

As per present study, out of 32 patients with bullous keratopathy in 21 patients ( 65.63% ) best corrected visual acuity was worse than 3/60 and in 11 patients ( 34.37% ) BCVA was between 3/60 to 6/60 before PK. After PK, 21 patients ( 65.63% ) were having BCVA between 6/18 to 6/60, 6 patients ( 18.75% ) were having BCVA worse than 3/60 and 3 patients ( 9.37% ) were having BCVA between 3/60 to 6/60 out of 32 patients.

TABLE – 8: Intraocular Pressure Before And After Pk

As per present study, IOP was high in 9 patients ( 28.12% ) and normal in 23 patients (71.87%) out of 32 patients with bullous keratopathy preoperatively. PK was done in those 9 patients after controlling IOP medically. After PK 13 patients (40.62%) were recorded with high IOP and 19 patients ( 59.38% ) with normal IOP out of 32 patients. 2 out of those 13 patients were recorded with high IOP inspite of the medical treatment and had undergone trabeculectomy at 6 months of follow up.

TABLE- 9: Postoperative Complications In 2 Year Follow Up

As per present study, postoperative complications were graft rejection in 15 patients (46.88%), uveitis in 13 patients (40.63%), graft failure in 6 patients (18.75%) , stitch infiltrations in 5 patients (15.62%), PED in 2 patients (6.25%) and PAS in 1 patient (3.12%) out of 32 patients who had undergone PK in 2 year of follow up. Signs of graft rejection in 11 patients and uveitis in 13 patients subsided after using topical and systemic steroids during 2 year of follow up. Stitches were removed in 5 patients with stitch infilteration and it subsided. PED in 2 patients was relieved by giving bandage contact lens.

TABLE – 10: Factors For Graft Failure At 2 Year Of Follow Up

As per the present study, factors responsible for graft failure in 6 patients were corneal vascularisation in 6 patients(100%), graft rejection in 4 patients (66.67%), anterior synechiae in 2 patients (33.33%) and posterior synechiae in 1 patient (16.67%) after PK at 2 year of follow up.

As per present study, out of 28 patients with bullous keratopathy had history of SICS in 10 patients (35.71 %), ECCE in 9 patients (32.15 %), Phacoemulsification in 3 patients (10.71 %), ICCE in 2 patients (7.14%) and in 4 patients (14.29 %) type of cataract surgery was not known.

By meta-analysis combination of several reported series from the literature, Drews et al¹⁰, 1978 derived an incidence of 3.2% +/- 4.3% corneal decompensation in 8515 cataract extractions with implant done in the 1960s and early 1970s. The majority of these were iris-supported or anterior

chamber IOLs with intracapsular extraction, although Tennant et al¹¹,1977 had reported an incidence of about 15% in a small series of anterior chamber IOLs with extracapsular extraction.

Stark et al¹², 1983 reported only a 0.1% rate in 1041 cases. Approximately 1-2% of post-cataract surgery patients develop pseudophakic bullous keratopathy. Rate of corneal edema occuring within 4 years postoperatively was estimated at 1.4% for intracapsular cataract extraction (ICCE) and 0.6% for extracapsular cataract extraction (ECCE) and Phacoemulsification¹³.

In a retrospective comparison Taylor et al¹⁴, 1983 reported PBK in 4.3% of 800 intracapsular cataract extractions with iris-supported IOL, aphakic bullous keratopathy in 0.8% of 3000 intracapsular cataract extractions without IOL, and PBK in 0.3% of 300 extracapsular cataract extractions with posterior chamber IOL. A similar estimate was derived from 15,500 cataract extractions in Switzerland in 1986 ¹⁵.

As per present study, out of 32 patients with bullous keratopathy in 21 patients ( 65.63% ) best corrected visual acuity was worse than 3/60 and in 11 patients ( 34.37% ) BCVA was between 3/60 to 6/60 before PK. After PK, 21 patients ( 65.63% ) were having BCVA between 6/18 to 6/60, 6 patients ( 18.75% ) were having BCVA worse than 3/60 and 3 patients ( 9.37% ) were having BCVA between 3/60 to 6/60 out of 32 patients.

Arentsen and Laibson et al^16,18,1982 advised retaining all stable IOLs at PKP, if possible, because of their finding in a nonrandomized series of 40 cases of 20/100 or better visual acuity in 86% of those with IOLs retained and 20/100 or better in 47% of those with IOL removed.

Cohen and associates¹⁹,1988 found 77% of 189 grafts clear at a mean follow-up of 15 months. At 1 year 11% had 20/40 or better acuity, but this improved to 31% by 2 years. A long-term follow-up study showed the greatest graft failure over retained anterior chamber IOLs (60%) and exchanged IOLs (20%) at 2 years, and the best vision with retained iris-supported, posterior chamber, or rigid anterior chamber IOLs. Vision and graft success have both been good when grafting over retained posterior chamber IOLs.

Jonas JB et al²⁰, 1995 had undergone a study to evaluate visual outcome after allogenic penetrating keratoplasty in 245 patients for keratoconus ( n=77), herpetic corneal scars ( n=29), non-herpetic corneal scars ( n=46), Fuchs endothelial dystrophy ( n=24), and pseudophakic/aphakic bullous keratopathy ( n=69). All patients were consecutively operated on by the same surgeon. The duration of follow-up had to exceed 1 year. In the study, increase in visual acuity and the best-corrected postoperative visual acuity were significantly ( P<0.01) highest for the patients with keratoconus (visual acuity increase from 0.16 to 0.69), followed by those with herpetic corneal scars (from 0.18 to 0.58), Fuchs corneal endothelial dystrophy (from 0.13 to 0.48), non-herpetic corneal scars (from 0.13 to 0.36), and finally patients with pseudophakic/aphakic bullous keratopathy (from 0.05 to 0.28).

As per present study, IOP was high in 9 patients ( 28.12%) and normal in 23 patients (71.87%) out of 32 patients with bullous keratopathy preoperatively. PK was done in those 9 patients after controlling IOP medically. After PK 13 patients (40.62%) were recorded with high IOP and 19 patients ( 59.38% ) with normal IOP out of 32 patients. 2 out of those 13 patients were recorded with high IOP inspite of the medical treatment and had undergone trabeculectomy at 6 months of follow up.

Another association between glaucoma and bullous keratopathy is that sometimes the cornea can decompensate after a laser treatment is performed to treat acute angle closure glaucoma. Typically if a drainage hole is made in the iris before acute angle closure happens, it does not cause corneal problems. Corneal complications during or immediately following ALI include corneal opacities and oedema, epithelial and endothelial burns²¹. The long-term significance of these complications is uncertain, with human and animal studies demonstrating variable results⁷⁶. Some predisposing risk factors that have been identified include a history of repeated intraocular pressure elevations, anterior segment inflammation, pre-existing corneal guttate, diabetes mellitus and higher levels of laser energy used to create a patent iridotomy²².

Patel SV et al²³, 2002 studied changes in the central endothelium and thickness of grafted corneas and the cummulative probability of developing glaucoma, of graft rejection, and of graft failure 15 years after penetrating keratoplasty in 500 consecutive penetrating keratoplasties by one surgeon. The cumulative probability of developing glaucoma was 20%.

Ing JJ et al²⁴, 2009 studied to investigate the changes in central corneal endothelial cells and corneal thickness in transplanted corneas from 5 to 10 years after penetrating keratoplasty. This study also aimed to investigate the development of glaucoma, graft rejection, and graft failure during the first 10 postoperative years. In the study it was found that by 10 years postkeratoplasty, 80 of the 394 patients had died and 68 grafts had failed. Of the remaining 246 patients, 119 (48%) returned for their 10-year examinations. The 10-year cumulative risk of glaucoma was 21%.

PK for bullous keratopathy having previously trabeculectomy reduces IOP control, particularly in eyes with non-functioning blebs. The rates of immune reaction- free grafts and graft survival after PK for bullous keratopathy having previously trabeculectomy are similar to those after PK for bullous keratopathy in eyes without glaucoma. Thus, the outcomes for PK in bullous keratopathy are good for patients having previously undergone trabeculectomy surgery, but it may be desirable that surgical procedures such as needling of the bleb and re- trabeculectomy be performed before PK in eyes with non- functioning blebs, even when IOP is under control with medication.

1. 1. Tool AR, Ambadkar S. Outcome of penetrating keratoplasty in pseudophakic bullous keratopathy, Indian J Clin Exp Ophthalmol. 2019;5(3):282-6.
   2. Shimazaki J, Amano S, Uno T, Maeda N, Yokoi N, the Japan Bullous Keratopathy Study Group. National Survey on Bullous Keratopathy in Cornea 2007; 26: 274–278.
   3. Rajesh Sinha, Namarata Sharma, Rasik Corneal blindness – present status. Cataract and Refractive Surgery Today. 2005;59-61.
   4. Matsuo H, Tomidokoro A, Suzuki Y, Shirato S, Araie Late-onset transconjunctival oozing and point leak of aqueous humor from filtering bleb after trabeculectomy. Am J Ophthalmol 2002; 133: 456–462.
   5. Ayyala RS. Penetrating keratoplasty and glaucoma. Surv Ophthalmol 2000; 45: 91–105.
   
   
   6. Patrick S, Carina K, Marie J Tassignon. Visual acuity after penetrating keratoplasty for pseudophakic and aphakic bullous keratopathy. J Cataract Refractive Surg 2003;29;482-6.
   7. Dada T, Agrawal A, Minudath KB, vanathi M, Choudhary S, Gupta V et al, Post penetrating keratoplasty glaucoma. Indian J Ophthalmol 2008;56;4; 269-77.
   8. Pricopie S, Istrate S, Voinea L, Leasu C, Paun V, Radu C. Pseudophakic bullous keratopathy. Rom J Ophthalmol 2017;61: 90–4.
   9. Mihail Z, Alina-Cristina S, Speranta S. Retrocorneal membranes after penetrating keratoplasty. Rom J Ophthalmol 2015;59: 230–4.
   10. Choi JS, Oh JY, Wee WR. A case of corneal endothelial deterioration associated with retained Descemet’s membrane after penetrating keratoplasty. Jpn J Ophthalmol 2009;53:653–5.
   11. Bourne RR, Minassian DC, Dart JK, Rosen P, Kaushal S, Wingate N. Effect of cataract surgery on the corneal endothelium: modern phacoemulsification compared with extracapsular cataract Ophthalmology. 2004;111(4):679-85.
   12. GI, Chiotoroiu SM, Secureanu FA, Purcarea VL, Zemba M. Use of amniotic membrane in bullous keratopathy palliative care. J Med Life. 2014;7(Spec Iss 2):88-91.
   13. Knezović I, Dekaris I, Gabrić N, Cerovski J, Barisić A, Bosnar D, Rastegorac P, Parać A. Therapeutic efficacy of 5% NaCl hypertonic solution in patients with bullous Coll Antropol. 2006;30(2):405-8.
   14. Gonçalves ED, Campos M, Paris F, Gomes JA, Farias Bullous keratopathy: etiopathogenesis and treatment. Arq Bras Oftalmol. 2008;71(6 Suppl):61-4.
   15. Mejía LF, Santamaría JP, Acosta Symptomatic management of postoperative bullous keratopathy with nonpreserved human amniotic membrane. Cornea. 2002;21(4):342-5.
   16. Zare M, Aslani M, Azimzadeh A, Esfandiari H, Valizadeh M. Indications and outcomes of repeat penetrating keratoplasty. Iran J Ophthalmol. 2011;23(2):44-50.
   17. Al-Yousuf N, Mavrikakis I, Mavrikakis E, Daya SM. Penetrating keratoplasty: indications over a 10 year Br J Ophthalmol. 2004;88(8):998- 1001.
   18. Schraepen P, Koppen C, Tassignon MJ. Visual acuity after penetrating keratoplasty for pseudophakic and aphakic bullous keratopathy. J Cataract Refract Surg. 2003;29(3):482-6.
   19. McVeigh K, Cornish KS, Reddy AR, Vakros G. Retained Descemet’s membrane following penetrating keratoplasty for Fuchs’ endothelial dystrophy: a case report of a post-operative complication. Clin Ophthalmol 2013;7:1511–4.
   20. Tyring A, Chang O, Jung H. Triamcinolone acetonide-assisted descemetectomy for retained Descemet membrane. COP 2018;9: 227–31.
   21. Sinha R, Vajpayee RB, Sharma N, Titiyal JS, Tandon R. Trypan blue assisted descemetorhexis
   
   

   for inadvertently retained Descemet’s membranes after penetrating keratoplasty. Br J Ophthalmol 2003;87:654–5.

   22. Schaefer F, Bruttin O, Zagrafos L, Guex-Corsier
   23. Bacterial keratitis: a prospective clinical and microbiological Study. Br J Ophthalmol 2001; 85:842-7.
   24. Vajpayee RB, Dada T, Saxena R, Vajpayee M, Taylor HR, Venkatesh P, et al. Study of the first Contact management profile of cases of infective keratitis: a hospital based study. Cornea 2000; 19:52-6.
   25. Upadhyay MP, Karamcharya PC, Koirala S, Shah DN, Shakya S, Shrestha JK, et The Bhaktapur eye study: Ocular trauma and antibiotic prophylaxis for the prevention of corneal ulcers in Nepal. Br J Ophthalmol 2001; 85:388-92.