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The role of initial 5-fluorouracil trabeculectomy in primary glaucoma. YK Dastur, S Dasgupta, A Chitale, P Firke, J Patel, S Sethi, V PatwardhanDept of Ophthalmology, KEM Hospital, Parel, Bombay, Maharashtra.
Correspondence Address: Source of Support: None, Conflict of Interest: None PMID: 0009136238
Sixty-eight patients with primary glaucoma involving 68 eyes were divided into two groups: Group I eyes were subjected to trabeculectomy (n = 38) and Group II eyes underwent trabeculectomy followed by subconjunctival injections of 5-fluorouracil (35 mg) (n = 30). After one year follow-up, Group I eyes exhibited reduction of mean intra-ocular tension from 45.7 mm Hg (pre-operative) to 16 mm Hg; optic disc cupping remained unchanged and 24/38 eyes (63%) were found to have field defects (19/38 i.e. 50% had preoperative field defects.) Group II eyes showed a reduction of mean intra-ocular pressure from 47.3 mmHg to 9.3 mmHg after one year. Mean cup disc ratio was lowered from 0.50:1 to 0.46:1 and 17/30 eyes (57%) which had field defects initially continued to exhibit the same. Complications in Group I and II eyes were shallow anterior chamber [8/38 eyes (21%) from Group I and 8/30 eyes (26%) from Group II], posterior synechiae formation in 10/38 eyes (26%) and 8/30 eyes (26%) and cataract progression in 13/38 eyes (34%) and 12/30 eyes (40%) respectively; only Group II eyes had transient superficial keratitis in 9/30 eyes (30%) and thin blebs in 6/30 eyes (20%). The use of 5-fluorouracil after trabeculectomy for primary glaucoma resulted in lowering of intra-ocular pressure, eliminated the need for antiglaucoma medications post-operatively, reduced the galucomatous cup size, and prevented progression of field loss without having a significantly increased complication rate. Keywords: Adult, Aged, Aged, 80 and over, Antimetabolites, pharmacology,therapeutic use,Fluorouracil, pharmacology,therapeutic use,Glaucoma, drug therapy,surgery,Human, Intraocular Pressure, drug effects,Middle Age, Trabeculectomy,
Antifibrosis regime prevents scarring external to the scleral flap, which is the most important cause of filtration failure after trabeculectomy[1]. Scarring at the level of the conjunctiva - Tenon's capsule - episceral interface leads to increased intra-ocular pressure years after surgery[1]. It has been accepted over the years that use of 5-fluorouracil (a pyrimidine analogue - an antimetabolite usually utilised for cancer therapy[2]) effectively inhibits fibroblastic proliferation in glaucomas with poor prognosis (viz aphakic glaucoma, neovascular glaucoma and inflammatory glaucomas)[2],[3],[4],[5],[6]. Of late, it has been shown that even patients of primary glaucoma operated for trabeculectomy usually have an intra-ocular pressure in the higher teens which effectively guards against visual field loss in only 50% patients[7],[8]. However, trabeculectomy with use of subconjunctival 5-fluorouracil post-operatively lowers the intra-ocular pressure in cases of primary glaucoma to single digits[1],[7],[8],[9],[10],[11],[12],[13]. This lowered intra-ocular pressure prevents any further visual field loss. The present study was carried out to confirm whether the use of 5-fluorouracil in eyes of primary glaucoma operated for trabeculectomy effectively lowers the intra-ocular pressure to a greater degree than after trabeculectomy alone. Further the effect of the lowered intra-ocular pressure on visual acuity, optic disc cupping, visual field loss and on the development of complications was studied.
Sixty- eight patients of primary glaucoma (with acute or chronic congestive glaucoma or chronic simple glaucoma) involving 68 eyes and who regularly attended prescribed follow-up for one year were selected for this prospective study. Patients with aphakic, neovascular, inflammatory glaucomas, having history of previously failed filtration surgery, receiving prolonged medical therapy for glaucoma and those who were treated elsewhere either medically or surgically were not included in this study. Of the 68 eyes, 38 were treated with trabeculectomy alone and those were called 'Group I eyes' in this study, while 30 eyes treated with trabeculectomy and subconjunctival 5-fluorouracil injection post-operatively were called as 'Group II eyes' in this study. The details regarding age and sex of patients belonging to these groups is presented in [Table - 1]. In short, 'Group I eyes' belonged to 20 males and 18 females and 14/38 of patients were in the age group of 51-65 years with the mean age of 51 years. 'Group II eyes' belonged to 17 males and 13 females and 14/30 of them were of age group 51-65 years (mean 50 years). The best corrected visual acuity was recorded for all the eyes in both the groups at the outset of the study. Primary glaucoma was diagnosed after complete ophthalmic examination including application tonometry, ophthalmoscopy, slit lamp examination, gonioscopy and kinetic perimetry. The patients subjected to trabeculectomy in both the groups were either the cases with acute glaucomatous attack or with intra-ocular pressure above 25 mm/Hg, optic disc cupping and with or without visual field changes. Secondary glaucoma was ruled out by slit lamp evidences of flare, KP's, rubeosis or ophthalmoscopic evidences of optic disc neovascularization. Blood pressure, blood sugar, sac patency were checked in all the patients prior to trabeculectomy. Operation was carded out after medical control of glaucoma by oral acetazolamide and topical 2% pilocarpine or 0.25% timolol or 0.5 % betaxolol. Watson's modification of trabeculectomy consisted of limbal based conjunctival and square shaped limbal based scleral flap. After trabecular tissue excision iridectomy was done in all the patients. Following operation all received oral antibiotics for three days, along with 1 % chloramphenicol eye ointment at night and 0.03% flurbiproper eye drops three times daily. After discharge, treatment at night with 1% chloramphenicol eye ointment was continued for 3 weeks while 0.03% flurbiprofen eye drops were continued thrice daily for 3 months. In addition, 'Group II eyes' were subjected to post-operative subconjunctival injections of 5-fluorouracil from 2nd post-operative day. 5-Fluorouracil (5 mg/0.1 ml) was injected subconjunctivally thrice (on alternate day) in the first week and again thrice in the second post-operative week. Only in patients below the age of 40 years and in those with thick Tenon's capsule another three subconjunctival injections of 5-fluorouracil were given in the third postoperative week. Thus 20 patients received 6 injections (30 mg of 5 fluorouracil) and 10 received 9 injections (45 mg of 5- fluorouracil). The mean dose of 5 fluorouracil administered was 35 mg. These 5-fluorouracil subconjunctival injections were given after instillation of 4% lignocaine eye drops in the conjunctival sac. A cotton tipped wooden applicator soaked in 4% lignocaine was placed on the bulbar conjunctiva at the site of injection for 3060 sec. A patient was instructed to direct his gaze away from the applicator so that the cornea was not abraded. Using a 2 ml syringe, 0.2 mi of 5-fluorouracil (50 mg/ml) was withdrawn, 26-gauge needle was attached and all the air bubbles in the needle were removed. At the chosen site 1800 away from the filtration bleb 0.1 ml was injected. Any reflux of 5-fluorouracil from the needle hole in the bulbar conjunctiva was prevented by pressing a dry cotton-tipped wooden applicator at the site of injection for 1 minute. Chloramphenicol eye ointment (1%) was applied to protect the cornea from further leakage of 5-fluorouracil. Even in patients with superficial punctate keratitis (non-confluent type) and shallow anterior chamber, the 5-flurouracil conjunctival injections were continued as usual. 'Group I eyes' were followed up at weekly intervals after discharge for 1 month, 2 weekly intervals for next 2 months and at monthly intervals for 1 year post-operatively. 'Group II eyes' treated with 6-9 subconjunctival 5-fluorouracil injections on out-patient basis (i.e. 1st 3 weeks), were followed up at 2 weekly intervals for the next 2 months and at monthly intervals for 1 year postoperatively. During follow-up the patients in both the groups were examined for best corrected visual acuity, intraocular pressure, cup-disc ratio and kinetic perimetry at 3 months and 1 year post-operatively. The patients with post-operative tension more than 20 mmHg were administered 0.5% betaxolol eye drops twice daily. Those with advanced cataracts underwent cataract extraction by extracapsular technique with posterior chamber implant using an upper quadrant corneal incision.
In 'Group I eyes' 15/38 (40%) eyes had acute or chronic congestive glaucoma and 23/38 eyes (60%) had chronic simple glaucoma. Pre-operatively 9138 eyes (24%) had 6/12 or better vision with mean pre-operative tension of 45.7 mmHg [Table - 2], mean cup disc ratio of 0.42:1 [Table - 3] and 19/38 eyes (50%) had glaucomatous visual field defects on kinetic perimetry. After 1 year of conventional trabeculectomy, these 38 'Group I eyes' showed that 8/38 eyes (21%) had 6/12 or better vision, with mean tension of 16 mmHg [Table - 2], mean cup disc ratio of 0.41:1 [Table - 3] and glaucomatous visual field defects in 24/38 eyes (63%). [Table - 2] and [Table - 3]. Further 'Group I eyes' showed complications such as shallow anterior chamber (8/ 38 eyes; 21 %) and posterior synechia (10/38 eyes; 26%). Though 7/38 (18%) eyes had shown presence of cataract pre-operatively, 1 year after trabeculectomy 13/38 eyes (34%) had cataract [Table - 4]. During this period of one year follow-up, 5 of these 13 cataracts had to be operated by extracapsular technique with posterior chamber lens implant. All these 5 operated cataracts had no operative complication and had visual recovery of 2 to 3 lines on Snellen's visual acuity chart. In 'Group II eyes' 10/30 eyes (33%) had acute or chronic congestive glaucoma and 20/30 (67%) had chronic simple glaucoma. Pre-operatively 7/30 eyes (23%) had 6/12 or better vision with mean pre-operative tension of 47.3 mmHg [Table - 2], mean cup disc ratio 0.50 A [Table - 3] and 17/30 eyes (57%) had glaucomatous visual field defects. After 1 year of trabeculectomy and mean dose of 35 mg of subconjunctival post-operative 5-fluorouracil, 8/30 eyes (26%) had 6/12 or better vision with a mean post-treatment tension of 9.3 mm Hg [Table - 2], mean cup disc ratio of 0.46:1 [Table - 3] and glaucomatous visual field defects in 17/30 eyes (57%), These 'Group II eyes' showed complications such as shallow anterior chamber in 8/30 eyes (26%); 9/30 eyes (30%) had superficial punctate keratitis (nonconfluent type), 6/30 eyes (20%) had thin filtration Blebs, 8/30 eyes (26%) had posterior synechia. While 7/30 (23%) had cataracts pre-operatively, after 1 year of operation 12/30 (40%) had cataracts [Table - 4]. Seven of these 12 cases were operated by extracapsular technique with posterior chamber lens implant. These 7 operated cataracts had no operative complications and had visual recovery of 2 to 3 lines on Snellen's visual acuity chart.
Antifibrosis regimen is presently combined with trabeculectomy for aphakic, neovascular, inflammatory glaucomas which have poor prognosis and for patients in whom filtration surgery has tailed[2],[3],[4],[5],[6]. Liebmann, et al[1], Wilson[7],[8],[9],[10] and Palmer[12] have stated that even for cases of primary glaucoma antifibrosis regimen should be used adjunctively with the trabeculectomy. Antifibrosis regimen consists of administration of anti-metabolite drug such as 5-fluorouracil, which is a inhibitor of DNA synthesis inhibitor and hence prevents fibroblastic proliferation at the site of the filtration bleb. The other drug used in the antifibrosis regimen is mitomycin[11],[12] which also inhibits DNA synthesis and is applied once during trabeculectomy to the operated site in the concentration of 0.2 mg/ml. Mitomycin is 100 times more potent in its antifibroblastic action than 5-fluorouracil. In this study we have evaluated the role of 5-fluorouracil as an adjunct to trabeculectomy for primary glaucoma. One year after the conventional trabeculectomy there was a 65% reduction of intra-ocular pressure to a mean value of 16 mmHg, while subconjunctival injections of 5-fluorouracil following trabeculectomy led to 80% reduction in intra-ocular pressure (9.3 mm Hg). Our findings thus confirms the reports in the literature[6],[9],[11],[13],[14]. While conventional trabeculectomy did not result in a reduction in the mean cup disc ratio, trabeculectomy followed by 5-fluorouracil injections effectively reduced the size of the galucomatous cup. Similar results have been reported by others[15],[16]. One year after the conventional trabeculectomy, 13% of the eyes had progressive field loss but none of the eyes treated with trabeculectomy and 5-fluorouracil injections had progressive visual field loss. This was also observed by other workers[7],[17],[18]. Trabeculectomy with adjunctive 5-fluorouracil did not result in a substantial loss of vision in our study in comparison with eyes subjected to trabeculectomy alone. However, other workers[7],[8],[9] have stated that the patients treated with trabeculectomy and 5-fluorouracil have low tension and consequently have fluctuating or seriously blurred vision. This study shows that the complication incidence is similar in both Group I and II eyes. However, superficial punctate keratitis (30%) and thin filtration blebs (20%) occurred only in eyes treated with adjunctive 5fluorouracil injections. These complications have been reported in other studies as well[3],[4],[9],[10]. Hence, this study confirms that the post-operative use of 5-fluorouracil is beneficial as it causes a greater lowering of intraocular pressure which consequently reduces the glaucomatous cup size, prevents progression of visual field loss and eliminates the need for postoperative anti-glaucoma medications. Wolner[7] has reported a 3% incidence of bleb related delayed endophthalmitis for trabeculectomies done from above post-operatively and treatment with 5-fluorouracil injections and 9.4% when performed from below. Other workers[3],[4],[5] have reported a delayed endophthalmitis due to thin and leaking filtration belbs in 1% of cases. In our study with one year follow-up none of the 30 'Group II eyes' have developed endophthalmitis, however 6/30 eyes (20%) had thin filtration blebs. Perhaps a long term study with a follow-up of over 5 to 10 years is necessary to determine whether these eyes subjected to trabeculectomy with adjunctive 5-Fluorouracil have a higher incidence of bleb related endophthalmitis compared with those subjected to trabeculectomy alone.
[Table - 1], [Table - 2], [Table - 3], [Table - 4]
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