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Combination intravitreal rituximab and methotrexate for massive subretinal lymphoma


Primary vitreoretinal lymphoma (PVRL), also known as primary intraocular lymphoma (PIOL), is a subset of primary central nervous system lymphoma (PCNSL), typically diffuse large B-cell lymphoma, which often manifests as posterior uveitis or sub-retinal pigment epithelial (RPE) infiltrates.1 PCNSL treatment includes radiation and chemotherapy; however, the optimal therapy for PVRL without CNS involvement is unknown.2 We report the efficacy of intravitreal rituximab and methotrexate in a patient with PVRL who presented with massive sub-retinal infiltration with RPE involvement.

Case report

An 83-year-old male patient presented with a 1-month history of progressive blurred vision OS. Visual acuities were 20/20 OD and hand motions OS. A relative afferent pupillary defect was present OS. Ophthalmic examination was normal OD. Trace vitritis and diffuse, confluent yellow-white subretinal infiltrates were seen OS (Figure 1). CBC, RPR, FTA-ABS, HIV, ACE, ESR, and chest CT scan were normal. Pars plana vitrectomy, subretinal aspiration biopsy, air-fluid exchange, endolaser, and 14% C3F8 instillation were performed.

Figure 1

Fundus photograph montage prior to therapy (a) showing massive yellow subretinal infiltrates with cystic-appearing spaces throughout the posterior pole and the majority of the peripheral retina. Fluorescein angiography revealing early mottled hyperfluorescence of the posterior pole with extensive leakage and perivascular staining (b, c). Spectral domain optical coherence tomography (SD-OCT) scan showing elevated neurosensory retina but no evidence of retinal infiltration (d). Cytopathological evaluation from a subretinal aspiration biopsy revealing a cellular infiltrate with cells larger than mature lymphocytes with condensed chromatin and multiple prominent nucleoli (e). Abundant necrotic cells are also seen (e, black arrows). Repeat fundus photograph montage (f) 2 months following initiation of combination rituximab and methotrexate therapy showing marked eradication of the subretinal lymphoma within the macula and retinal periphery. These areas resolved completely by the final 18-month follow-up. Horizontal macular SD-OCT scan showing resolution of the previously seen neurosensory elevation with some RPE thickening and subretinal fibrosis (g, yellow arrows).

Cytopathology revealed lymphomatous infiltrates with condensed chromatin and multiple nucleoli. Flow cytometry showed CD20+ staining. IgH gene rearrangement studies demonstrated monoclonal restriction consistent with diffuse large B-cell lymphoma.

Brain MRI and CSF studies were negative for CNS disease. Following neuro-oncology consultation regarding treatment options including chemotherapy, blood–brain barrier disruption, and radiation, systemic therapy was deferred by the patient. Monthly intravitreal injections of rituximab (1 mg/0.1 ml) and methotrexate (400 mcg/0.1 ml) for 3 months were undertaken. Rapid regression of the subretinal lesions was observed by 2 months and visual acuity improved to finger counting at 3 feet. The retinal examination was stable at 18 months with no evidence of CNS involvement.


Rituximab is a chimeric monoclonal antibody targeting the CD20+ B-cell marker, while methotrexate inhibits folate metabolism and DNA synthesis. Intravitreal monotherapy for PIOL has been described,3, 4, 5 while combination intravitreal methotrexate 200 mg/0.05 ml (half the standard dose) and rituximab 1 mg/0.1 ml has been reported once previously.4 The rationale for combination therapy stems from conventional combination chemotherapy for systemic diffuse large B-cell lymphoma, which may include high-dose systemic methotrexate and intrathecal rituximab.6 The complete ocular remission in our patient following three doses of combination methotrexate and rituximab at 18-months follow-up suggests that this dosing strategy warrants further investigation. Further studies are needed to determine its long-term efficacy, and CNS surveillance with the aid of a neuro-oncologist is advisable.


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The authors declare no conflict of interest.

Additional information

Funding and Support: This research was supported by an unrestricted grant to the Casey Eye Institute from Research to Prevent Blindness, New York, NY. Dr Yeh has received support from the Heed Ophthalmic Foundation and the Ronald G Michels foundation.

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Yeh, S., Wilson, D. Combination intravitreal rituximab and methotrexate for massive subretinal lymphoma. Eye 24, 1625–1627 (2010).

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