A Rare Case of Acute Hemorrhagic Retinopathy Following Intravitreal Melphalan Injection for Persistent Vitreous Seeds in Retinoblastoma

Abstract

Purpose:

This report describes a case of acute occlusive hemorrhagic complication after intravitreal melphalan for vitreous seeds in retinoblastoma.

Methods:

A case report is presented.

Results:

Intravitreal melphalan has been used extensively for vitreous seeds in retinoblastoma. Although melphalan is relatively safe at optimal doses, it can sometimes cause inadvertent complications like hemorrhagic events if the drug is administered close to the retina or in more pigmented eyes. We report a case of a 5-month-old patient with bilateral retinoblastoma who underwent enucleation of the right eye and 2 intravitreal melphalan injections in the left eye (20 µg/0.02 mL) at a 1-month interval for persistent vitreous seeds. After the second injection, there was a sudden decrease in the child’s visual acuity in the left eye, and the retina showed multiple intraretinal hemorrhages and diffuse chorioretinal atrophy.

Conclusion:

Intravitreal melphalan may cause acute hemorrhagic complications after intravitreal use for retinoblastoma seeds, especially in pigmented eyes.

Introduction

Intravitreal chemotherapy for management of vitreous seeds in retinoblastoma was first introduced in 1961 by Ericson and Rosengren, who reported the use of intravitreal thiotepa in 6 eyes. ¹ However, it did not gather steam for nearly 4 decades because of anticipated local and systemic tumor spread. It gained popularity only after the use of intravitreal melphalan was reported in 2012 for the management of persistent vitreous seeds in retinoblastoma with good success. ^{2 -6} The most common adverse effect of intravitreal melphalan is localized, peripheral chorioretinal toxicity in the quadrant of injection, as described by Munier and colleagues. ⁴ Here we describe a case of acute hemorrhagic retinopathy with diffuse chorioretinal atrophy following intravitreal injection of melphalan.

Methods

Case Report

A 5-month-old boy was diagnosed with bilateral retinoblastoma, International Intraocular Retinoblastoma Classification group E in the right eye and group C in the left eye. At this stage, we could assess that the child was not fixating or following light with his right eye and was following light with the left eye. The right eye was prephthisical with anterior segment tumor seeds, whereas the left eye showed a large endophytic tumor at the posterior pole with focal vitreous seeds (in a dust-like configuration) along with a small, flat tumor in the superior periphery with a localized outpouching into the vitreous cavity (Figure 1A).

Figure 1.

(A) Fundus photograph of the left eye showing a large tumor over the posterior pole with an endophytic lesion located superiorly. (B) Persistent vitreous seeds near the superior endophytic lesion and regressing posterior pole tumor.

After 3 cycles of systemic chemotherapy, the child underwent enucleation of the right eye and cryotherapy to the peripheral lesion in the left eye. At age 8 months, there were persistently active vitreous seeds in the left eye (Figure 1B), for which 2 intravitreal injections of melphalan (20 µg/0.02 mL; Alkacel, Celon) were given at a 1-month interval along with ongoing systemic chemotherapy. Cryotherapy was applied at the injection site, the needle was withdrawn post each injection, and the eyeball was thoroughly jiggled to uniformly distribute the drug.

Within 10 days of the second intravitreal injection, the parents noted that the child was suddenly not looking at or responding to light. We confirmed the same, that the child was not fixating or following light with the left eye. Fundus examination revealed a completely regressed (type 1) calcified prior tumor lesion and vitreous seeds as well as diffuse chorioretinal atrophy, multiple superficial and deep intraretinal hemorrhages, a pallid retinal appearance, and extensive retinal pigment epithelium (RPE) mottling (Figure 2A). Ultrasound B-scan of the left eye showed no evidence of a posterior vitreous detachment. The child had completed 6 cycles of systemic chemotherapy and subsequently did not need further intravitreal injections or additional focal therapy up to the last follow-up at age 27 months. The child continued to maintain the same clinical status for the next 2 monthly follow-up visits until age 15 months (Figure 2B), when he regained fixing and following light vision in the left eye. At the final follow-up at age 27 months, we documented best-corrected visual acuity in the left eye as 6/24 Snellen.

Figure 2.

Fundus photograph of the left eye showing the regressing tumor with diffuse chorioretinal atrophy and areas of superficial and deep retinal hemorrhages at (A) 10 days post second injection and (B) at age 15 months.

Conclusions

Several studies have reported good outcomes for regression of vitreous seeds using intravitreal chemotherapy with melphalan, with reported success rates up to 100%. ^5,6 Based on the safety and efficacy profile studied in animal models, assisted by electroretinography (ERG) measurements, a dose of 20 to 30 µg melphalan is generally recommended for injection, with doses less than 10 µg having a subtherapeutic effect and greater than 50 µg causing a significant reduction in ERG amplitudes and significant retinal toxicity. ^2,7 Even at the recommended dosage, intravitreally administered melphalan can be associated with ocular complications, the most common being focal RPE mottling (salt-and-pepper retinopathy) around the meridian of injection, where the drug may be most concentrated. Each injection is reported to be associated with an average amplitude of ERG reduction of 5.3 µV on ERG. ^8,9 Other less common complications include transient focal vitreous hemorrhage, transient hypotony, transient retinal hemorrhage, optic disc edema, and frank hemorrhagic retinal necrosis. ⁶ An average of 3 to 5 melphalan injections may generally be required in most eyes.

Apart from the cumulative number of injections, other factors that have been shown to contribute to retinal toxicity include the dosage and concentration of melphalan injected, concomitant intra-arterial chemotherapy with melphalan within 1 week of intravitreal injection, and increased ocular pigmentation. ^{6 -9}

An increased risk of melphalan-related retinal toxicity in pigmented eyes of Asian populations, including India, has been previously reported. ^8,9 Apart from the fact that eyes with more pigmentation may absorb higher levels of melphalan, resulting in retinal and choroidal toxicity, melphalan may also have a direct toxicity on RPE cells and cause typical angiographic features, as has been demonstrated in preclinical studies. ⁷ Chao et al have reported diffuse chorioretinal atrophy in the quadrant of injection following a single 8-µg dose of intravitreal melphalan. ¹⁰ Considering this toxicity profile, there are emerging reports of preferential use of intravitreal topotecan over melphalan for management of vitreous seeds, showing reasonable outcomes with much less incidence of retinal toxicity. ¹¹ However, there are no documented cases of hemorrhagic occlusive retinal vasculopathy from India.

Severe hemorrhagic occlusive retinal vasculopathy may rarely occur following injection of melphalan, probably owing to injection into the retrohyaloid space (paravitreous injection) in the setting of a detached posterior hyaloid. ^12,13 The proposed mechanisms reported in the literature include the induction of a posterior vitreous detachment following a prior intravitreal injection and/or an endophytic tumor with vitreous seeds that causes apical disruption of the internal limiting membrane–posterior hyaloid complex. ^12,14 Hence, severe hemorrhagic occlusive retinal vasculopathy can potentially be avoided by visualizing the needle tip behind the lens under the operating microscope and injecting slowly to form a cloud of drug in the midvitreous cavity. Ultrasonography to identify a posterior hyaloid detachment as well as shaking of the eyeball with 2 forceps or a cotton-tip applicator post injection to diffuse the drug uniformly into the vitreous cavity have been proposed to avoid this complication. ¹² Most centers also suggest performing a prior paracentesis, which not only acts as an antireflux maneuver but also allows a higher volume and hence a more diluted concentration of the drug to be injected. ^4,15

Our patient had received intravitreal melphalan at a dose of 20 µg/0.02 mL with careful dosage calculation by the treating oncologist. There was no evidence of posterior hyaloid detachment on ultrasonography after the injection. Moreover, no such complications were noted after the first injection. Previously authors have reported the safe use of 20 µg/0.02 mL intravitreal melphalan in a large case series. ¹⁶ The rationale behind this practice was that it allowed the injection of a smaller volume of drug, thereby reducing the chances of vitreous reflux through the needle tract and further minimizing the risk of tumor cells or seeds gaining extraocular access. It also allowed avoiding a prior paracentesis in that series of eyes.

Higher concentration of injected melphalan could have been a contributing factor precipitating the patient's acute occlusive hemorrhagic event, especially considering that the RPE mottling occurred around the meridian of injection, not unlike most cases as mentioned earlier, where the drug was likely to be most concentrated. Hence, following the complication, we have switched to using a more diluted injection of 20 µg/0.04 mL in our cases.

A limitation of our report is an absence of further assessment with a fundus fluorescein angiography. To the best of our knowledge, there are no similar case reports of such acute hemorrhagic occlusive retinopathy following melphalan injection from the Indian subcontinent.

To summarize, although intravitreal melphalan is a relatively safe drug at the proper dosage, potentially blinding complications must be kept in mind and precautions should be exercised while counseling and planning for the injection, especially in pigmented eyes.