Mitomycin C is a potent alkylating agent that can cause cellular damage via cross-linking of DNA.1 Because of its antiproliferative effect on subconjunctival fibroblasts, MMC is commonly used as an adjunct to ophthalmic surgeries in an effort to improve surgical outcomes.1 In 1990, Chen et al first described the use of MMC in glaucoma filtering surgery. Despite the now routine use of MMC, the ideal route of administration, dosage, and exposure times is debated between surgeons and there is a narrow window for toxicity.1 The most common application of MMC is a dosage of 0.2 to 0.4 mg/mL applied topically for 2 minutes.1 Although MMC use in glaucoma surgery reduces the risk of bleb failure, complications are well-recognized. These include overfiltration and wound leak, increased risk of shallow anterior chamber, choroidal effusion, hypotonous maculopathy, and suprachoroidal hemorrhage.1 Late complications include bleb leaks and subsequent endophthalmitis.1 There are very few reports of MMC-related posterior segment toxicity. We describe a case of retinal toxicity presumed secondary to MMC use during glaucoma filtering surgery.
This is an observational case report of a single patient diagnosed with presumed MMC-related retinal toxicity. Complete ophthalmic examination and multimodal imaging, including color fundus photos, optical coherence tomography (OCT), fundus autofluorescence, and fluorescein angiography. The study was declared exempt by the institutional review board of Northwestern University. This research followed the tenets of the Declaration of Helsinki.
A 62-year-old man, with a history of primary open angle glaucoma treated with topical drops, presented with complaints of progressively worsening vision in the left eye following a trabeculectomy with MMC. One month prior, the patient underwent an uncomplicated glaucoma filtrating surgery. At the time, the patient was anesthetized with monitored anesthesia care and a retrobulbar block, consisting of 50:50 2% lidocaine and 0.75% Marcaine. The retrobulbar block was performed by the attending ophthalmologist, without complication. At the start of the case, 0.2 mL of 0.2 mg/mL of mitomycin C was injected into the sub-Tenon space approximately 10 mm posterior to the limbus. The remainder of the fornix-based trabeculectomy was completed without complication. The patient was discharged home with topical prednisolone acetate 1%, gatifloxacin, and tobramycin-dexamethasone ointment.
On postoperative Day 1, best-corrected visual acuity (BCVA) of the left eye was 20/20, intraocular pressure was 22 mmHg, and the anterior segment was notable for 2+ cells. At subsequent visits, BCVA declined and anterior segment examination was notable for increasing keratopathy.
On postoperative Day 10, BCVA dropped to counting fingers and intraocular pressure was 8 mmHg. The patient endorsed a history of bending with sudden eye pain. Anterior segment examination was notable for a shallow anterior chamber and ophthalmoscopy demonstrated superior choroidal effusion. Optical coherence tomography demonstrated retinal thinning with prominent disorganization and irregularity of the outer retinal layers (Figure 1). The patient was treated with Cyclogyl and Neosynephrine. On postoperative Day 17, BCVA was light perception. Ophthalmoscopy showed resolution of choroidal effusion, but significant retinal arteriolar attenuation. The patient was referred to the retina service for presumed central retinal artery occlusion.
In the retina clinic, we noted BCVA left eye light perception with intraocular pressure of 11 mmHg. The anterior segment examination had 1–2+ cell in the solid anterior vitreous, but no active vitritis or vitreous haze. Ophthalmoscopy showed diffuse disc pallor, absence of the foveal light reflex, and marked diffuse vascular attenuation with featureless peripheral retina (Figure 3A). Fluorescein angiography was performed with profound lack of choroidal and retinal vascular perfusion. In late frames, flow through nasal vessels was visible without leakage (Figure 3B). Optical coherence tomography showed diffuse retinal thinning with some preservation of nasal parafoveal inner retinal layers, but diffuse loss of outer retinal layers, including subfoveally (Figure 2A). The right eye was normal. The patient was diagnosed with presumed retinal toxicity secondary to mitomycin C use.
Two weeks later, the patient experienced flashes of light in the left eye. Ophthalmoscopy demonstrated new shallow diffuse subretinal fluid without identifiable retinal breaks. Optical coherence tomography showed increased retinal thinning with subretinal fluid (Figure 2B). Tiny hyperreflective opacities were seen overlying the retinal pigment epithelium and within subretinal fluid.
Two months later, approximately postoperative Month #3, findings were unchanged.
At most recent follow-up, approximately post-operative Month #15, BCVA remained light perception and intraocular pressure was 2 mmHg. Anterior segment examination was notable for a flat superior conjunctival bleb, no active cell or flare, and a dense nuclear white cataract with mild pseudophakodonesis. There was no view to the posterior segment. Ultrasonography confirmed continued total retinal detachment.
During the initial postoperative course, the patient's subjective and objective visual decline was initially attributed to corneal pathology given the familiar side effect of toxic keratopathy with repeated 5-fluorouracil use. However, when profound vision loss ensued, a thorough posterior segment examination was performed revealing marked arteriolar attenuation and optic nerve pallor. Because these posterior segment findings have not been reported with subconjunctival 5-fluorouracil use, the patient was diagnosed with a vascular occlusion and urgently referred to retina. Our initial impression, based largely on the patient's lack of systemic vascular risk factors, the timing of visual decline following intraocular surgery, and prominent early loss of the outer retina on OCT imaging, suggested this was more likely a case of retinal toxicity. Of the three medications (lidocaine, 5-fluorouracil, and MMC) used peri-operatively, only MMC has the potent toxicity to account for this clinical picture.
To our knowledge, there are only two case reports of inadvertent intraocular injection of mitomycin C in a human subject. Mirshahi et al2 described complications following intravitreal injection of 0.05 mL of 0.2% mitomycin C solution in a diabetic patient with macular edema and mild retinopathy. Two days after injection, the retina was featureless with arteriolar attenuation. Fluorescein angiography only showed large retinal vessels, without leakage, and ERG confirmed undetectable responses. The patient underwent 23 g pars plana vitrectomy. Follow-up showed early retinal edema and intraretinal hemorrhages with subsequent increase in arteriolar attenuation and atrophic features, including retinal thinning and the development of subretinal fluid. In another case, Ryoo et al3 documented inadvertent intraocular injection of mitomycin C in a patient with no preinjection eye pathology. This patient also underwent a vitrectomy. Review of OCT images at time of the initial event and 6-month follow-up demonstrate cystoid macular edema with progressive loss of outer retinal layers. The details of this case, including route of administration and dosage, are unclear.
In a case of presumed MMC-related retinal toxicity, Nuyts et al4 describe a patient with complicated anterior segment history who underwent uncomplicated trabeculectomy with MMC. The MMC was used topically (0.5 mg/mL applied as sponge to scleral woundbed for 5 minutes) following formation of the scleral flap.4 At postoperative week 3, the patient underwent uncomplicated subconjunctival bleb needling with 0.3 mL of 0.5 mg/mL MMC. After 5 days, BCVA dropped to hand motion and ophthalmoscopy revealed narrowed arterioles, diffuse peripheral hemorrhages, and a whitish retina. Fluorescein angiography showed no flow in mid phase. The profound retinal damage was hypothesized secondary to diffusion of MMC from the subconjunctival space into the vitreous cavity, via the scleral flap. The patient was believed to be particularly susceptible because of lack of a posterior capsule and a prior vitrectomy.
There are only a few animal studies evaluating the potential side effects of intravitreal MMC. Kawashima et al5 studied the effect of different concentrations of MMC, including 0.2, 0.3, and 0.4 mg/mL, on the rat retina after intravitreal or anterior chamber injection. This study demonstrated profound histopathologic changes following intravitreal injection of 0.4 mg/mL of MMC. The earliest changes included degeneration of Muller cells at 2 days and degeneration of retinal pigment epithelium and outer segments at 4 days. By Day 7, there were significant changes in outer nuclear layer, some retinal pigment epithelium cells were replaced by macrophages, and the choriocapillaris was occluded.
Peyman et al6 studied the effects of various antineoplastic drugs, including MMC, in the rabbit eye as potential treatments for proliferative vitreoretinopathy. In this study, 0.1 mL of MMC ranging from 1.0 to 8.0 μg, was injected into the mid vitreous cavity. Toxicity secondary to the antineoplastic agents was generally described as whitish reactions in the retina, surface hemorrhages, and optic atrophy seen as early as 3 days following injection. By 10 days, the retina was pale and there was diffuse damage to the outer retina and retinal pigment epithelium.
As the retinal abnormalities in our case were not recognized until approximately one month after glaucoma surgery, we did not see any retinal features consistent with the reported earliest findings of MMC-related toxicity, including retinal edema or intraretinal hemorrhages. However, we reviewed OCT on postoperative Day 10, which clearly documents early significant disruption of the outer retina, consistent with animal studies (Figure 1). By postoperative month one, the patient had profound retinal damage with OCT showing increased retinal thinning (Figure 2A) and no flow through retinal or choroidal vessels on angiography (Figure 3B), consistent with both case reports and animal studies. At subsequent follow-up, the patient remained at no light perception and developed a shallow retinal detachment, consistent with the case reported by Mirshahi et al.2
The greatest limitation of this report is understanding the manner by which the patient developed MMC-related toxicity. The dosage used in this case is commonly used during routine trabeculectomy surgeries. Single flash ERG studies by Kawashima et al5 following intravitreal injection of 0.2 mg/mL and 0.4 mg/mL of MMC demonstrated loss of B wave amplitude 7 days following intravitreal injection of 0.4 mg/mL MMC, but no significant change in B wave amplitude compared with stimulus intensity following intravitreal injection of 0.2 mg/ml. In contrast, Mirshahi et al2 clearly document profound retinal toxicity following 0.05 mL intravitreal injection of 0.2 mL/mg MMC in a human subject.
Therefore, given that the concentration of MMC used in our case is well within the accepted range for topical use, we believe that the evidence strongly supports intravitreal MMC as the cause of retinal toxicity. We believe that the most likely cause was inadvertent intraocular injection of MMC. Simple diffusion of MMC into the intravitreal space via any route is less likely given that the use of adjunct MMC in glaucoma filtering surgery, even in complicated eyes, is a common surgical practice and cases of MMC-related toxicity are rare. In this case, the surgeon was an experienced glaucoma specialist. This highlights the caution ophthalmologists should use in using MMC during filtering surgery.
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