Subacute Toxic Pigmentary Retinopathy after Intravitreal Ganciclovir Injection: A Case Report

Dear Editor,

Intravitreal ganciclovir injection is a common treatment for cytomegalovirus (CMV) retinitis. As systemic ganciclovir administration is associated with severe systemic morbidity, intravitreal ganciclovir injection has been commonly used within the dosage of less than 2.0 mg/0.1 mL, which has proven to be safe in several studies [1]. When used with an overdose or an accumulated number of injections, toxic crystalline retinopathy and photoreceptor damage have been reported as side effects of ganciclovir intravitreal injection [2]. Here, we present a case of aggressive toxic pigmentary retinopathy after a single intravitreal ganciclovir injection within the standard dose.

This study was approved by the Institutional Review Board of Seoul St. Mary’s Hospital, The Catholic University of Korea (No. KC23ZISI0854). Written informed consent for publication of the research details and clinical images was obtained from the patient.

A 45-year-old woman undergoing peripheral hematopoietic stem cell transplantation for acute lymphocytic leukemia referred from the hematologic department for positive CMV polymerase chain reaction (PCR) (7,398 IU/mL) in plasma, receiving oral valganciclovir. She had been treated with an induction and consolidation chemotherapy, and immunosuppressive treatment for skin graft-versus-host disease. Among the hematologic agents administered, there have been no reported cases of them causing outer retinal toxicity or retinal pigment epithelium (RPE) dysfunction in humans. The patient had phakic eyes with intact zonules and no history of intraocular surgeries, including cataract surgery or vitrectomy. In her left eye, initial corrected visual acuity (VA) was 20/20, and a single peripapillary whitish inflammatory lesion was found on fundus examination (Fig. 1A, 1B). Despite the absence of apparent CMV retinitis, a single preemptive dose of ganciclovir (2.0 mg/0.1 mL) was administered via intravitreal injection while concurrently performing a real-time CMV PCR assay on aqueous humor, which was finally confirmed to be negative. The intravitreal injection was administered slowly and with consistent pressure by an experienced retinal specialist. Additionally, focal laser photocoagulation was performed on both eyes to address inferior, old, shallow, localized retinal detachments (RD) with multiple tears, discovered postinjection, covering 10 optic disc areas.

Fig. 1

Images of the case. (A) Clinical timeline for a case after initial intravitreal ganciclovir injections is given. (B–J) Representative images and results from the acute lymphoblastic leukemia patient. (B) A single peripapillary whitish lesion detected on wide fundus photography in the left eye at initial visit. (C,D) A wide range of pigmentary atrophy in outer retinal layer and retinal pigment epithelium (RPE) with a localized retinal detachment observed in the left eye on widefield fundus photography and fundus autofluorescence (AF) at 1 month after intravitreal ganciclovir injection. (E) One-year post-intravitreal ganciclovir injection, AF revealed advanced, enlarged, and clumped panretinal atrophy. (F) An extensive speckled pattern of RPE defect observed in the early phase of fluorescent angiography in the left eye. (G) Outer retinal layer thinning with multiple hyperreflective foci on optical coherence tomography. (H) Humphrey automated 24-2 visual field test showed severe total visual field depression in the left eye. (I) A standard full-field electroretinogram (ERG) revealing nearly flat amplitudes of scotopic and photopic responses in the left eye. (J) No paraneoplastic autoantibodies were detected in the specimen of anterior chamber aqueous humor, which was acquired to exclude cancer-associated autoimmune retinopathy. CMV = cytomegalovirus; PCR = polymerase chain reaction; AC = anterior chamber; VA = visual acuity; FP = fundus photograph; OCT = optical coherence tomography; FAG = fluorescein angiography; IVTA = intravitreal triamcinolone; MD = mean deviation; PSD = pattern standard deviation; OP = oscillatory potentials.

After 1-month postinjection, the VA in the left eye was 20/40, and the peripapillary infiltration resolved. However new RPE depigmentation was observed on fundus photography and fundus autofluorescence (AF) (Fig. 1C, 1D). Additionally, multiple hyperreflective foci appeared in the outer retinal segment on optical coherence tomography (OCT) (Fig. 1G). After another month, extensive speckled pattern of RPE defects was observed during the early phase of fluorescent angiography (Fig. 1F). A Humphrey automated 24-2 visual field test revealed a severely depressed visual field (Fig. 1H). After 11 months from the injection, VA was 20/2,500 and standard full-field electroretinogram showed nearly flat amplitudes of both scotopic, photopic responses (Fig. 1I). No paraneoplastic autoantibodies were detected through Line Immuno Assay (ImmunoBlot) in the serum, to exclude cancer-associated autoimmune retinopathy (Fig. 1J). One year postinjection, AF demonstrated progressive enlargement and clumping of RPE atrophic areas. (Fig. 1E). Despite several steroid injections, there was no further recovery in the VA or fundus examinations.

Unlike the conventional crystalline retinopathy reported by Kim et al. [2], our case exhibited a gradual disease progression characterized by pigmentary atrophic changes in fundus exams, accompanied by multiple outer-retinal hyperreflective foci in OCT.

In the present case, broad localized RD was suggested to be a risk factor for aggressive toxic retinopathy. First, the elevated accumulation of ganciclovir in the subretinal space may result in more pronounced damage to the RPE and photoreceptor cells, particularly in patients with retinal tear and detached retina. Compared to transport via a transretinal mechanism along a vitreochoroidal gradient [3], direct migration of ganciclovir into the subretinal space could be more toxic. Second, similar characteristics have been documented in patients undergoing treatment with deferoxamine, an iron-chelating agent [4]. Daruich et al. [5] illustrated an elevation in iron levels within the vitreous and subretinal fluid of patients with RD, and their in vivo animal model demonstrated that the neurotoxic effects of iron led to photoreceptor cell death. We postulated that the existing RD could potentially synergize with ganciclovir toxicity, leading to a cascade of catastrophic degenerative changes in the retina due to combined iron and ganciclovir toxicities.

In conclusion, ophthalmologists who prescribe intravitreal ganciclovir for CMV retinitis should be aware of the occurrence of a rare but catastrophic complication within the RPE and photoreceptor cells, even with a standard concentration of 2.0 mg/0.1 mL. Potential risk factor, such as localized retinal detachment, should be considered when deciding on the protocol for ganciclovir treatment.