Acute Hemorrhagic Retinopathy following Intravitreal Melphalan Injection for Retinoblastoma: A Report of Two Cases and Technical Modifications to Enhance the Prevention of Retinal Toxicity

Abstract

Aims: To report the occurrence of acute hemorrhagic retinopathy following intravitreal melphalan injection for retinoblastoma. Methods: This is a retrospective case series of 2 patients with retinoblastoma treated with intravitreal melphalan for vitreous seeding who developed acute hemorrhagic retinopathy. Results: Patient 1 is a 6-month-old female with bilateral retinoblastoma (Group D right eye and Group B left eye) treated with 4 cycles of systemic chemotherapy and 2 intravitreal melphalan injections in each eye. Patient 2 is a 10-month-old male with unilateral Group D retinoblastoma treated with 6 cycles of systemic chemotherapy and 2 injections of intravitreal melphalan. At the 1-week follow-up after the second injection, both patients had an acute hemorrhagic retinopathy that resulted in chorioretinal toxicity with a sharp demarcation line between the normal and abnormal retina. At the last follow-up (22 and 12 months, respectively), there was total tumor control and resolution of vitreous seeding in both patients. Conclusions: Although intravitreal melphalan injection is effective for vitreous seeding in eyes with retinoblastoma, acute hemorrhagic retinopathy and diffuse chorioretinal atrophy is a possible complication of this treatment modality. Given the clinical findings observed in these patients, the development of this retinal toxicity most likely results from a retrohyaloid overdose. Consequently we suggest preventive measures aimed at limiting the risk of retrohyaloid injection.

Integrated Treatment during the Intravitreal Melphalan Era: Concurrent Intravitreal Melphalan and Systemic Chemoreduction

“…While the grading system proposed by Munier [14] was not used in this (and other) studies, “widespread” likely indicates at least greater than grade 3. It has been suggested that doses > 30 µg may increase toxicity [16], although acute and diffuse toxicity have been described recently by Chao et al [26] after only 1 low-dose injection and by Aziz et al [27] at doses lower than 30 µg. Although our study observed a higher rate of retinal toxicity than prior ocular oncology literature, our cohort is small, and, additionally, the variation in the determination of retinal toxicity limits any direct comparison with the clinical grading we utilized as proposed by Munier [14].…”

“…The injection procedure closely adheres to the protocol outlined by Munier and colleagues [13-15] and previously published [6]. Although a standardized dosage of melphalan has not been fully established due to the relative novelty of the treatment modality, previous publications support the usage of 20–40 µg.…”

Posterior Vitreous Detachment and the Associated Risk of Retinal Toxicity with Intravitreal Melphalan Treatment for Retinoblastoma

“…Per the initial protocol described by Munier et al [4], an ultrasound biomicroscopy is indicated to evaluate the quadrant of injection prior to intravitreal injection of chemotherapy. Further, after the report from Aziz et al [14] hypothesized that PVD may play a role in severe toxicity, a B-scan was recommended before each intravitreal injection, and this protocol is followed at our center.…”

“…While targeted use of IVM for vitreous seeding has virtually eliminated external beam radiation therapy and its associated risk of second cancers [10, 11], this new modality is not without its own risk of toxicity. Studies have demonstrated a dose-dependent toxic effect on retinal pigment epithelial cells [2, 9, 12] ranging from localized changes which have no effect on vision to diffuse chorioretinal toxicity with irreversible vision loss [3, 13, 14]. IVM has also been associated with anterior segment ocular toxicity, including cataract, anterior chamber inflammation, and iris atrophy [15].…”

“…It has been hypothesized that the presence of a posterior vitreous detachment (PVD) may play a role in the development of severe, Grade 5 retinal toxicity following IVM [14]. This hypothesis was generated from 2 cases of acute hemorrhagic toxicity wherein a sharp demarcation was noted between the normal and affected retina, suggesting that the melphalan may have been inadvertently injected in the retrohyaloidal space, thus concentrating the drug against the retina.…”