Introduction

Endophthalmitis is defined as severe eye inflammation involving anterior and posterior segments due to an infectious agent. It is a sight-threatening condition that can occur as a complication of ocular surgery or trauma, or following systemic infection. Common signs of endophthalmitis include reduced visual acuity, conjunctival injection, presence of cells and flare in anterior chamber and vitritis (Durand 2013). Early treatment following correct diagnosis is essential to optimise the visual outcome. 

The systemic use of tissue plasminogen activator (tPA) has been approved since 1988 for thrombolysis in coronary artery disease. Since then, this drug has been extended to other indications, including the eye. Its safety and effectiveness for treatment of fibrin-related complications of ocular inflammation including endophthalmitis was reported in multiple studies (Damji et al. 2001; Wu & Wang 2009; Riaz et al. 2006). Severe anterior segment inflammation does not only cause poor visualisation of the posterior segment, synechiae that is formed can also leads to secondary pupillary block. Traditionally, laser iridotomy is the treatment of choice for pupillary block. This procedure however, may potentially aggravate the pre-existing inflammatory condition. Moreover, in severe fibrin reaction, anterior chamber details could not be distinguished thus hindering laser iridotomy procedure. We report the use of recombinant tissue plasminogen activator (rtPA) as a first line treatment for secondary pupillary block in a case of severe endophthalmitis. As a fibrinolytic agent, it accelerates the clearance of fibrin in endophthalmitis, thus preventing devastating complications of endophthalmitis such as loss of vision. 

Case Report

A 69-year-old man with background of diabetes mellitus underwent a complicated phacoemulsification surgery which was converted to extra capsular cataract extraction (ECCE) followed by implantation of intraocular lens (IOL) on his right eye in a private ophthalmology centre. Patient received topical Dexamethasone 0.1% and topical Moxifloxacin 0.5% post-operatively. At 2 weeks post-operatively, he developed acute endophthalmitis and was given intravitreal Vancomycin, Ceftazidime and Dexamethasone once. However, he defaulted subsequent follow-up and presented to us 2 weeks later with a complaint of right eye redness and pain. Examination revealed visual acuity of hand movement with severe inflammation in the anterior chamber with no fundus view. IOL was noted to be subluxated inferiorly. B-scan showed loculations in the vitreous but no retinal detachment. Intraocular pressure (IOP) was 4 mmHg on the right eye. 

Repeated intravitreal Ceftazidime (Duopharma, Malaysia) 2.25mg/0.1ml, Vancomycin (Mylan Lab, India) 1mg/0.1ml and Dexamethasone (Duopharma, Malaysia) 0.4mg/ 0.1ml were given. He was also started on oral Moxifloxacin (Bayer, Germany) 400 mg daily, in combination with 2 hourly dose of topical Moxifloxacin 0.5% (Alcon, Singapore), 6 hourly Dexamethasone 0.1% (Alcon, Belgium) and daily Atropine 1% (Alcon, Belgium). The cornea was very hazy with the presence of Descemet striations. He was prepared for pars plana vitrectomy. On the following day, worsening of the anterior chamber reaction was noted causing seclusio pupillae with shallow anterior chamber. Iris bombe and iridocorneal touch were present 360-degrees (Figure 1), while the IOP was still 12 mmHg. Following topical anesthesia, 25 micrograms of rtPA, Alteplase (Boringer, Germany) in 0.1 ml of saline was injected intracamerally through the inferonasal limbus using a 30-gauge needle. One hour following injection, the fibrin reduced, anterior chamber was deeper, iris bombe resolved completely and pupil was slightly larger (Figure 2). The patient was subsequently arranged for IOL explantation and vitrectomy. Surgery was uneventful, and the patient was left aphakic. Upon discharge, his vision improved to 6/36 assisted with +10D lens. Vitreous culture did not grow any organism.

Discussion

Acute endophthalmitis is an ocular emergency which requires prompt diagnosis and treatment. The most important component of therapy is intravitreal antibiotic injection. However, even with correct timing of starting antibiotic therapy, intense inflammation may lead to severe fibrin reaction in anterior and posterior segment which may result in posterior synechiae, seclusio pupillae, peripheral anterior synechiae, iris bombe, and secondary angle-closure glaucoma (Durand 2013).

Alteplase is a recombinant form of tPA, which is a proteolytic enzyme in serine protease family found on endothelial cells. It is essential for fibrinolysis and acts as thrombolytic agent. Tissue plasminogen activator converts plasminogen to plasmin once it bounds to fibrin, which subsequently promotes fibrin degradation (Damji et al. 2001). Tissue plasminogen activator dissolves clots rapidly, within minutes to hours and it also has a short biological half-life. The use of alteplase for acute cases of ischemic stroke, myocardial infarction, massive pulmonary embolism, and occlusion of central venous access devices (CVADs) is permitted by Food and Drug Administration (FDA). Although it is not routinely used in ophthalmology, the high efficacy of intracameral rtPA has been reported for treatment of anterior chamber fibrin formation following cataract extraction, trabeculectomy, combined cataract and glaucoma surgery, penetrating keratoplasty, as well as vitrectomy (Damji et al. 2001; Georgiadis et al. 2003; Wedrich et al. 1997). Moreover, the effectiveness of rtPA to treat severe fibrin reaction was also demonstrated in case of endophthalmitis (Wu & Wang 2009), and recalcitrant anterior uveitis (Patrick et al. 2018). Thus intracameral rtPA is probably underused in our fraternity.

In the present case, the clinical indication for rtPA was secondary pupillary block with iris bombe in a severely inflamed eye. A randomised prospective study by Heiligenhaus et al. (1998) revealed significant reduction of synechiae and successful synechiolysis after intracameral tPA injection in patients with intraocular fibrin formed following cataract surgery (Heiligenhaus et al. 1998). Intracameral rtPA was also noticed to be effective in decreasing the incidence of pupillary dysfunction due to the posterior synechiae formation and fibrin deposition at pupillary region, as shown in the study (Heiligenhaus et al. 1998). In another reports, fibrin membrane dependent pupillary block was shown successfully treated with intracameral tPA injection (Akcetin et al. 2015; Yoshino et al. 2012). These reports suggest the use of rtPA as the primary treatment for both fibrin reactions after cataract surgery and secondary pupillary block. 

Meanwhile, Wu & Wang (2009) reported enlargement of pupillary size 24 hours after rtPA injection in endophthalmitis patients. In addition to previous studies, this study also demonstrated the effectiveness of using intracameral injection of rtPA in endophthalmitis, which eventually facilitates vitreous and fundus examination, including vitrectomy if needed. This will be a very valuable advantage for these type of patients as vitrectomy can be challenging not only if the cornea is hazy due to the severe anterior chamber reaction, low IOP and even worse if the pupil is small. Manipulation of pupil during surgery will eventually induce intense inflammation post operatively.

In terms of timing of rtPA injection following fibrin formation, various literatures reported successful fibrinolysis within hours of injection (Riaz et al. 2006; Damji et al. 2001; Erol et al. 2003). In a study by Dotan et al. (2014), they demonstrated the therapeutic effect of rtPA in refractory toxic anterior segment syndrome (TASS) patients. In their case, it is of different mechanism whereby the TASS is caused by breakdown of blood-aqueous barrier thus the initial hypothesis is that injection administration later (after 16 days of cataract surgery) would show better outcome than earlier intervention (within 10-15 days of cataract surgery) (Dotan et al. 2014). However, the study has proven that regardless the timing of injection following cataract surgery, fibrinolysis rate as well as visual acuity improvement have no statistically significant different. Successful fibrinolysis was shown in all subjects in the report. In our case, successful fibrinolysis was observed as early as one hour post rtPA injection. In case of fibrin membrane pupillary block, the rtPA injection should be given as soon as fibrin formation is noted because further delay could raise IOP and further optic nerve damage.

Conclusion

Intracameral rtPA, which is alteplase, is useful in replacing the conventional use of laser peripheral iridotomy in treating fibrin membrane pupillary block.