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Intracameral recombinant tissue plasminogen activator (r-tPA) for refractory toxic anterior segment syndrome
  1. Assaf Dotan1,
  2. Igor Kaiserman2,
  3. Israel Kremer1,3,
  4. Rita Ehrlich1,
  5. Irit Bahar1,3
  1. 1Department of Ophthalmology, Rabin Medical Center, Petach Tikva, Israel
  2. 2Department of Ophthalmology, Barzilai Medical Center, Ashkelon, Israel
  3. 3Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
  1. Correspondence to Dr Assaf Dotan, Department of Ophthalmology, Rabin Medical Center, Beilinson Campus, Petach Tikva 49100, Israel; docdotan{at}gmail.com

Abstract

Aims To investigate the therapeutic effect of recombinant tissue plasminogen activator (r-tPA) in patients with refractory toxic anterior chamber segment syndrome after cataract surgery with posterior chamber intraocular lens implantation.

Methods This prospective cohort study was performed from May 2010 to November 2011 at a tertiary university-based medical centre. Forty patients (40 eyes) with an anterior chamber fibrin reaction after cataract surgery were treated with intracameral injection of r-tPA (25 µg/0.1 mL) following failure to respond to conventional treatment with intensive topical and subconjunctival steroids. Outcome measures were best-corrected visual acuity, clearance/recurrence of the fibrin reaction and complications. Corneal endothelial cell counts were evaluated before and after r-tPA injection (n=6).

Results Intracameral r-tPA injection was administered 10–49 days after cataract surgery; mean was 20.3±9.6 days after surgery. At 1 day after treatment, complete clearance of the fibrin reaction was observed in 32 patients (80%) and partial clearance in 8 (20%). At the 1-month evaluation, the reaction had completely resolved in 95% of patients. Mean visual acuity improved from 0.61±0.38 logMAR before treatment to 0.45±0.37 logMAR 1 month later (p=0.06). There were no statistically significant differences in improvement in visual acuity and fibrinolysis rate by time of r-tPA injection after surgery (10–15 days, n=16 vs 16–49 days, n=24). There were no cases of increased intraocular pressure or endophthalmitis following the procedure.

Conclusions Intracameral injection of 25 µg r-tPA is safe and effective for the treatment of refractory fibrin reaction after cataract surgery.

  • Anterior Chamber
  • Inflammation

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Introduction

Toxic anterior segment syndrome (TASS) is a sterile inflammatory reaction of unknown incidence after anterior segment surgery. It usually occurs acutely, but delayed onset has been reported as well.1 The incidence is variable with reported rates between 0.22%2 and 0.8%3 in different series. The most common finding is diffuse limbus-to-limbus corneal oedema secondary to damage from the toxic insult to the endothelial cell layer. Widespread breakdown of the blood–aqueous barrier is another hallmark of the condition, associated with fibrin in the anterior chamber and hypopyon in 75% of cases. TASS may be differentiated from infectious endophthalmitis by the absence of vitreitis.4

The mainstay of treatment for TASS is intense topical prednisolone acetate 1% drops administered every 1–2 h. Patients are carefully followed, especially during the first days of treatment, to ensure that the inflammatory condition is stabilising and not worsening.5 Close monitoring is particularly required in the presence of fibrinous membranes because of the increased potential for glaucoma and long-term trabecular damage.4 The inflammation usually resolves with treatment, but in severe cases, there may be long-lasting corneal oedema and glaucoma secondary to trabecular meshwork damage.1

In cases of failure of intense topical steroids, several studies have proposed other treatment modalities, including anterior chamber washout,4 Nd:YAG fibrin membranotomy6 ,7 and intracameral injection of recombinant tissue plasminogen activator (r-tPA).8–14 The use of r-tPA, a serum protease activated by fibrin, is based on the rationale that catalysing the conversion of plasminogen into plasmin induces fibrin breakdown into fibrinogen and disappearance of the fibrin reaction. The aim of the present study was to investigate the efficacy of intracameral r-tPA injection in the management of refractory TASS after cataract extraction surgery.

Methods

Setting and patients

A prospective cohort study was conducted from May 2010 to November 2011 at a tertiary, university-affiliated, medical centre. The sample included 40 consecutive patients (40 eyes) with an inflammatory fibrinous reaction in the anterior chamber after cataract extraction surgery with posterior intraocular lens (IOL) implantation who failed to respond to conventional treatment with intensive topical and subconjunctival steroids. In one patient, cataract surgery was combined with corneal transplantation.

Treatment

Initial treatment in all cases consisted of topical prednisolone acetate 1% drops administered every 1–2 h in addition to fluoroquinolone drops qid, and atropine sulfate 1% drops bid for 1 week. If no improvement was documented, a single injection of subconjunctival steroids was added to the regimen (CelestoneChronodose, Schering-Plough N.V., Belgium). If there was still no response, an intracameral injection of 25 µg/0.1 mL r-tPA was administered.

Recombinant tissue plasminogen administration

The rt-PA preparation (Actilyse, Boehringer Ingelheim Limited, UK) was diluted under sterile conditions to a concentration of 25 µg/0.1 mL, distributed into insulin syringes and stored at −80°C. Before treatment, the syringes were defrosted at room temperature. Injections were performed either as an office procedure, with the patient seated at the slit lamp, or in the operating room if patient compliance was limited or in cases of late-onset TASS with application of the injection more than 21 days following surgery.

Prior to r-tPA injection, topical anaesthesia and 0.5% povidone iodine drops were applied, and the eyelids were opened with a lid speculum. Aqueous humour was drained from the anterior chamber, and 0.1 mL of r-tPA was injected intracamerally using a 30-gauge needle through one of the incisions created during cataract extraction. Following the procedure, fluoroquinolones and prednisolone acetate 1% drops were instilled qid for 1 week. Thereafter, the corticosteroid drops were gradually tapered down over 1 month.

Study procedure

Background variables were collected prior to treatment. Patients were evaluated for a fibrin reaction or complications at 1 day (24 h), 1 week and 1 month following t-PA injection using slit-lamp biomicroscopy. Intraocular pressure (IOP) was measured by Goldmann applanation tonometry, and best-corrected visual acuity (BCVA) was tested using a standard Snellen chart. Findings at each time point were compared with baseline values and with the previous evaluation. Corneal endothelial cell counts were performed in some patients before and after r-tPA injection.

Results

The study group consisted of 18 men and 22 women of mean age 76±10 years. The right eye was affected in 17 patients and the left eye in 23. Twenty-eight patients (70%) received subconjunctival steroids before r-tPA treatment, at a mean of 11.5±6.14 days after surgery. Injection of r-tPA was performed at a mean of 20.3±9.6 days after surgery (range 10–49 days). Mean duration of follow-up after r-tPA injection was 32±18 days (range 2 weeks to 4 months).

The outcome of intracameral r-tPA treatment is shown in table 1.

Table 1

Outcome of intracameral r-tPA injection in 40 patients with refractory fibrin reaction

At 1 day after the injection, the fibrinous membrane in the anterior chamber was completely dissolved in 32 patients (80%) (figures 1 and 2) and partially dissolved in 8 (20%) (figures 1 and 2). At 1 month, the fibrinous membrane was completely dissolved in 38 patients (95%). The difference in the percentage of patients with fibrin remaining in the anterior chamber between the 1-day, 1-week and 1-month examination was statistically significant (p<0.0001 for all).

Figure 1

Anterior segment photograph demonstrating a significant fibrinous reaction 3 weeks after phacoemulsification and posterior chamber intraocular lens (IOL) implantation. Note the dense fibrinous membrane formation on the IOL. Access the article online to view this figure in colour.

Figure 2

Anterior segment photograph 24 h after intracameral recombinant tissue plasminogen activator injection demonstrating a clear intraocular lens without a fibrinous membrane. Access the article online to view this figure in colour.

Mean BCVA before surgery (0.61±0.38 logMAR) was decreased at 1 day after r-tPA injection (0.67±0.41 logMAR). Thereafter it improved to 0.47±0.37 logMAR at 1 week (p=0.10) and 0.45±0.37 logMAR at 1 month (p=0.06) (figure 3). Eight patients had a pre-existing eye disease that could have potentially contributed to a worse visual outcome: age-related macular degeneration (n=2), diabetic retinopathy (n=2), corneal opacity (n=1) or cystoid macular oedema (n=5). When they were eliminated from the analysis, mean BCVA decreased at 1 day from 0.56±0.36 logMAR at baseline to 0.6±0.37 logMAR, and then improved significantly to 0.41±0.35 at 1 week and 0.36±0.3 at 1 month (p=0.002 compared with 1 day).

Figure 3

Visual acuity before and after intracameral recombinant tissue plasminogen activator r-tPA injection.

Mean endothelial cell count, measured in six patients, was 1830±589 cells/mm2 before r-tPA injection and 1891±723 cells/mm2 1 week later. None of the patients had an increase in IOP or endophthalmitis following r-tPA treatment.

Table 2 presents the comparison of studied parameters by time of r-tPA treatment following cataract surgery: 10–15 days in 16 patients (early treatment) or 16–49 days in 24 patients (late treatment). There were no statistically significant differences between these subgroups in final BCVA, rate of fibrinolysis or changes in IOP.

Table 2

Outcome of r-tPA injection in 40 patients with refractory fibrin reaction by time of treatment after cataract surgery

Discussion

Surgical ophthalmic procedures, including cataract extraction, cause a breakdown of the blood-aqueous barrier, which results in protein leakage and cell reaction in the aqueous humour. These are manifested clinically as flare and cells. The postoperative formation of fibrinous membrane is explained physiologically by the conversion of intracameral fibrinogen to fibrin and the enzymatic action of thrombin.15 The fibrin and fibrinogen, together with chemotactic factors, induce white blood cell activity and adherence, resulting in additional capillary permeability. This leads to a vicious cycle of fibrin formation. Rates of fibrin formation after cataract surgery vary between 2% and 8% in the general population.9 ,14 Findings of a significant decrease in endogenous tPA activity in the first days after cataract surgery with IOL implantation led to the suggestion that the process of fibrin formation may be associated with fluctuations in tPA in the aqueous humour of pseudophakic eyes.16 It takes 1–3 months for the blood–aqueous barrier to recover after routine extracapsular cataract surgery with posterior chamber IOL implantation.17

TASS is a non-infectious condition characterised by postoperative inflammation and fibrin formation. Depending on its severity and cause, TASS may cause damage to the iris, which leads to pupillary dilatation or irregularities. Glaucoma may occur secondary to the toxicity-induced damage to the trabecular meshwork.1 ,10 Other potential long-term vision-threatening complications include corneal decompensation, chronic cystoid macular oedema, capsule phimosis and posterior capsular opacification. Fibrinous membrane formation in the anterior chamber may result in reduced visual acuity, photophobia, pupillary block,6 ,18 ,19 IOL dislocation or a fixed miotic pupil resistant to topical mydriatics.20

The treatment of refractory fibrinous reactions after cataract surgery by disruption of the membrane with an argon18 or Nd:YAG laser6 or surgical dissection and removal of the membrane poses a risk of increased anterior chamber inflammation and recurrent fibrin formation. A promising alternative is intracameral injection of r-tPA, which can also alleviate peripheral anterior synechiae. Using a rabbit model of intraocular fibrin formation, Snyder et al8 were the first to show (1987) that r-tPA promotes fibrin dissolution with minimal toxicity. Since then, r-tPA has been used in humans for anterior chamber fibrinolysis after intraocular surgeries, in dosages of 3–25 µg,9–17 with high effectiveness and safety.11 ,14 ,19

In the present series, complete fibrinolysis was observed in 80% of the patients within 24 h of r-tPA injection. There were no cases of elevated IOP or endophthalmitis. By 1 month, 95% of patients showed complete resolution of the fibrinous reaction. Fibrin first forms when thrombin cleaves fibrinogen to fibrin which polymerises. The fibrin then is further cross-linked by factor IIX and is relatively resistant to fibrinolysis. This could explain why fibrinolysis was delayed in eight patients (20%) and was incomplete in two patients (5%).

To the best of our knowledge, this is the second largest report, after Heiligenhaus et al,11 of r-tPA use for fibrinolysis in the anterior chamber associated with cataract surgery. They studied the effect of 10 µg tPA in patients with severe intracameral fibrin only 2–8 days after cataract extraction.11 When analysing the visual acuity data, we noticed that elimination of patients with pre-existing eye disease showed a further visual acuity improvement. Preoperative mean logMAR BCVA in the group with no other pathology was 0.56±0.36 vs 0.61±0.38 in the whole group. Respectively, logMAR BCVA improved from 0.67±0.41 to 0.6±0.37 1 day after r-tPA injection, from 0.47±0.37 to 0.41±0.35 at 1 week and from 0.45±0.37 to 0.36±0.3 at 1 month following r-tPA injection.

Interestingly, despite the high rate of complete resolution of the fibrinous reaction already after 1 day, improvement in visual acuity was documented only at 1 week and 1 month of follow-up. Indeed, visual acuity was slightly worse at the 1-day examination compared with the preoperative value. We assume that this early finding was related to the presence of inflammatory mediators in the anterior chamber soon after the r-tPA injection. This is the first time that corneal endothelial cell counts are reported following intracameral r-tPA administration. No significant cell loss was demonstrated. Because intracameral r-tPA treatments in the present study were used only in cases refractory to conventional treatment, the first injections were performed 10 days after cataract surgery, and the mean interval from surgery was 20.3±9.6 days. Given that TASS may be due to a breakdown of the blood–aqueous barrier, we hypothesised that injections administered later (16–49 days after surgery) would yield better outcomes and less recurrence than earlier intervention (10–15 days after cataract surgery). However, we found no statistically significant differences in these factors by time of injection.

In conclusion, the present study shows that 25 µg r-tPA is safe and effective for the treatment of refractory fibrin reactions after cataract surgery. Intracameral application of r-tPA hastens fibrin absorption and may help to avoid the complications associated with long-standing intraocular inflammation. Further investigations are needed to determine the optimal dosage and long-term effect of treatment, including changes in corneal endothelial cell counts.

References

Footnotes

  • Competing interests None.

  • Ethics approval The study was approved by the Rabin Medical Center Ethics Committee (0206-12-RMC).

  • Provenance and peer review Not commissioned; externally peer reviewed.