Vitreoretinal lymphoma (VRL) is recognized as a lymphocytic malignancy marked by the involvement of the uvea, retina, vitreous cavity, and optic nerve. The occurrence of infiltrative optic neuropathy (ION) due to lymphoma is infrequent, with estimates suggesting it constitutes approximately 5% of primary central nervous system (CNS) lymphomas [1]. ION attributable to lymphoma, specifically optic nerve lymphoma, is categorized into four distinct types: solitary optic nerve lesions, optic nerve lesions with concurrent CNS disease, optic nerve lesions with systemic disease, and optic nerve lesions associated with VRL [1]. Among them, optic nerve lymphoma stemming from VRL is considered rare. Notably, in prior case reports concerning primary VRL, the majority already exhibit concurrent CNS lesions at the onset of ION [2].

Recent reports have highlighted that hyperreflective deposits in the intraretinal and subretinal pigment epithelial (RPE) layers, as identified through optical coherence tomography (OCT), may serve as early indicators of VRL [3, 4]. While there are accounts of VRL progressing from such OCT findings, no studies have yet demonstrated progression to ION in the context of VRL [3]. In present report, we detail a unique case of ION instigated by VRL, characterized by pre-onset hyperreflective deposits in the intraretinal and sub-RPE layers, a phenomenon hitherto unreported.

We presented an 87-year-old Japanese female, who had hypertension, hyperlipidemia, and osteoporosis as her past medical history. At 5 months before onset, she noticed a decline of the right visual acuity. After that, she visited ophthalmology clinic because her visual acuity was progressively deteriorated to counting finger. In clinic, uveitis complicated with vitreous opacification (VO) was revealed, and subtenon triamcinolone acetonide was injected for treatment. Although visual acuity and VO were improved after treatment, she was referred to Osaka University Hospital for detailed examination. Visual acuity was 20/50 and 20/30 in the right and let eyes, respectively. Intraocular inflammation and VO were not detected. There were yellowish-white deposits in the right macula, and OCT showed hyperreflective deposits in the intraretinal and sub-RPE layers at the same area. (Fig. 1A, B) However, there were no other abnormal findings through other ophthalmologic examination. The left eye had no abnormal findings. We decided to observe in our hospital as uveitis of undetermined causes at this time.

Ophthalmological appearance and images at first visit. (A) A fundus image shows yellowish-white deposits in the right macula. (black arrow). (B) An OCT image shows hyperreflective deposits in the intraretinal and sub-RPE layers. (white arrows)

One month later, she visited our hospital with acute visual exacerbation. The right visual acuity was hand motion and left visual acuity was 20/30. Intraocular pressure was 18 mmHg and 17 mmHg in the right eye and let eyes, respectively. She had a right relative afferent pupillary defect. Goldmann visual field perimetry was full in the left eye, but a large dense central scotoma was present in the right eye. (Fig. 2A, B) While slit lamp examination was normal in the left eye, optic disc swelling with disc hemorrhage was revealed in the right eye. Yellowish-white deposits in the right macula was not changed before 1 month. (Fig. 2C) Any intraocular inflammation and VO were not detected in both eyes. OCT showed prominent disc swelling with intraretinal and subretinal fluid. (Fig. 2D) The left eye was normal in the above ophthalmic imaging examination. (Fig. 2E, F)

Ophthalmological appearance and images at the disease onset. (A) Goldmann visual field perimetry is full in the left eye. (B) Goldmann visual field perimetry finds that a large dense central scotoma within a 30-degree range and arcuate peripheral vision remains only on the nasal side of the right eye. (C) A fundus image shows optic disc swelling with disc hemorrhage in the right eye. (white arrow) Yellowish-white deposits in the right macula was not changed before 1 month. (black arrow). (D) An OCT image shows prominent disc swelling with intraretinal and subretinal fluid in right eye. (E) A fundus image shows no abnormal findings in the left eye. (F) An OCT image shows no abnormal findings in the left eye

We speculated the possibility of ION, because she had the previous medical history with VO complicated by unknown uveitis. However, a magnetic resonance imaging (MRI) of the head without enhancement did not show hyperintensity and swelling of the optic nerve as well as intracranial lesions. (Fig. 3A, B) In addition, there was neither VO nor intraocular inflammation at this time. We considered that retinal biopsy for macular or papillary lesions were highly invasive for visual function, so decided to hospitalize the patient for steroid pulse treatment for prominent disc swelling at first. One week after hospitalization, VO occurred and we speculated that hyperreflective deposits in the intraretinal and sub-RPE layers progressed to ION with VRL. Therefore, we decided to perform 25-gauge microincision vitrectomy for vitreous collection in an emergency. Vitreous specimens were processed for cytology, flow cytometry, and gene rearrangement with the Registration Examination and Analysis Description (READ) system [5]. A histological examination indicated a lot of atypical cells with large nuclear/cytoplasm ratios suspected malignant lymphoma. (Fig. 4A) Findings from the flow cytometry analysis revealed the infiltration of cells positive for CD45, CD19, and CD20, but not CD10 and CD22. Furthermore, the surface immunoglobulin cytochemical analysis revealed monotypic light chain expression restricted kappa chain. (Fig. 4B) The results of a gene rearrangement analysis were positive for the immunoglobulin heavy locus. Finally, after consideration of all the clinical examinations, a diagnosis was made of ION with vitreoretinal B-cell lymphoma. Although systemic chemotherapy was considered due to CNS involvement, it was deemed inappropriate given the advanced age of the patient. Instead, local intravitreal methotrexate injections were administered and the patient’s condition was monitored with regular brain MRI. This treatment plan was discussed in detail and approved by the patient.

Cranial MRI images at the disease onset. (A) A T2-weighted non-enhancement MRI image of the head in coronal scanning shows no abnormal findings. (B) A T2-weighted non-enhancement MRI image of the head in axial scanning shows no abnormal findings

Results or intraoperative histology and flow cytometry. (A) A histological examination on hematoxylin and eosin-stained indicates a lot of atypical cells with large nuclear/cytoplasm ratios suspected malignant lymphoma. (B) Findings from the flow cytometry analysis shows that the infiltration of cells positive for CD45, CD19, and CD20, but not CD10 and CD22. Furthermore, the surface immunoglobulin cytochemical analysis revealed monotypic light chain expression restricted kappa chain

Intravitreal methotrexate injections were administered a total of 6 times at intervals of about 2 weeks due to repeated corneal epithelial keratopathy. One month after operation, optic disc swelling and subretinal fluid were markedly improved. (Fig. 5A, B) At the time of the last visit (6 months after surgery), VO and optic disc swelling had disappeared. (Fig. 5C) In OCT image, hyperreflective deposits in the intraretinal and sub-RPE layers were remaining. (Fig. 5D) Careful observation was continued, but no recurrent findings including MRI was observed, and visual acuity in the right eye at the last visit improved to 20/50.

Ophthalmological appearance and images after the start of treatment. (A) A fundus image at postoperative 1 month shows remarkable improvement of disc swelling and subretinal fluid. There are still residual disc hemorrhages. (B) An OCT image at postoperative 1 month shows intraretinal and subretinal fluid are disappeared. Hyperreflective deposits in the intraretinal and sub-RPE layers are remaining. (C) A fundus image at last visit (postoperative 6 month) shows completely remission of disc swelling, disc hemorrhage, and subretinal fluid. (D) An OCT image at last visit (postoperative 6 month) shows stable findings without recurrence. Hyperreflective deposits in the intraretinal and sub-RPE layers are remaining. (white arrows)