A rare case of infiltrative optic neuropathy caused by vitreoretinal lymphoma with hyperreflective deposits in the intraretinal and subretinal pigment epithelial layers prior to the disease onset

Abstract

Background

To describe a rare case of infiltrative optic neuropathy (ION) caused by vitreoretinal lymphoma (VRL) with hyperreflective deposits in the intraretinal and subretinal pigment epithelial (RPE) layers before the disease onset.

Case presentation

An 87-year-old Japanese female, previously treated for unexplained uveitis in the right eye, was referred for further evaluation. Despite the absence of intraocular inflammation or vitreous opacification (VO), yellowish-white deposits were noted in the macula, and OCT revealed hyperreflective deposits in the intraretinal and sub-RPE layers. One month later, she returned with acute visual deterioration. Optic disc swelling and disc hemorrhage were observed without VO or intraocular inflammation. Magnetic resonance imaging (MRI) showed no abnormalities. One week later, VO developed and we performed a 25-gauge vitrectomy. Cytology, flow cytometry, and gene rearrangement confirmed malignant B-cell lymphoma. The diagnosis of ION secondary to VRL was made, and intravitreal methotrexate injections were administered a total of 6 times. Six months postoperatively, VO and optic disc swelling resolved, and visual acuity improved to 20/50, with no recurrence on MRI.

Conclusions

Although there were reports on VRL advanced from hyperreflective deposits in the intraretinal or sub-RPE layers, there have been no studies that these OCT findings has progressed to ION with VRL. When differentiating optic neuropathy, OCT may assist in the diagnosis by evaluating intraretinal and sub-RPE findings.

Background

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.

Case presentation

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.

Fig. 1.

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)

Fig. 2.

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.

Fig. 3.

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

Fig. 4.

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.

Fig. 5.

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)

Discussion and conclusions

In the complex landscape of diagnosing optic neuropathy, the rare entity of ION associated with VRL poses significant challenges. This difficulty is accentuated in cases which the pathological manifestation is confined to the ocular structure, devoid of VO. Our case highlights an instance which the onset of VO, albeit fortuitously post-disease onset, facilitated a vitreous biopsy. This critical intervention enabled the early identification of ION driven by vitreoretinal B-cell lymphoma. The occurrence of VO not only served as a pivotal diagnostic marker but also underscored the imperative for ophthalmologists to maintain a high level of vigilance for the subtle signs indicating of VRL’s early stages.

OCT emerges as a cornerstone in the nuanced diagnosis of optic neuropathy, offering a window to detect early manifestations of VRL. Reports in the literature have elucidated that the appearance of hyperreflective deposits in the intraretinal and sub-RPE layers as preliminary indicators of the disease, potentially denoting an uptick in disease activity [6]. However, the specificity of these signals warrants careful consideration, given their presence in other retinal conditions such as diabetic retinopathy and age-related macular degeneration [7, 8]. This necessitates a discerning approach to differentiate these conditions accurately. Moreover, the presence of hyperreflective deposits across various retinal layers, as seen in cases of CNS malignant lymphoma, accentuates their potential as biomarkers for early VRL detection [4]. In the presented case, the precursory detection of hyperreflective deposits in the intraretinal and sub-RPE layers, against a background of a medical history devoid of diabetes but inclusive of VO from unclassified uveitis, was instrumental in guiding the provisional diagnosis towards ION. Compared to the past report which showed changes in hyperreflective deposits over time, especially in this case, there was a rapid progression of the disease in a short period, resulting in a prominent retinal edema [6]. As a result, it is unclear exactly which layer of hyperreflective deposits progressed to ION. In future research, it is necessary to investigate what characteristics of hyperreflective deposits are likely to progress to ION.

The absence of VO presents a diagnostic challenge, as the yield for malignancy through cytological examination significantly diminishes from 47.1% in the presence of VO to merely 10.0% without VO [9]. Moreover, considering the high risk associated with retinal biopsies of the optic disc or macula, particularly in terms of visual function, such procedures are deemed highly invasive. Therefore, present case to delay surgical intervention until the manifestation of VO was strategically prudent. This approach aimed to enhance the accuracy of the malignancy diagnosis while concurrently mitigating the risk to the patient’s visual function.

In discussing MRI findings relevant to ION, it is important to note that even without contrast enhancement, MRI can reveal thickening of the optic nerve, a hallmark of this condition [10]. Lymphoma infiltration and optic neuritis present similarly on MRI, showing low to iso-intensity on T1 and high intensity on T2-weighted images [10]. Contrast-enhanced MRIs often show significant enhancement in optic nerve lymphoma cases, with literature noting up to 88% of cases displaying this feature [11, 12]. From the above, it is considered that the diagnosis can be made by MRI regardless of contrast enhancement if optic nerve lymphoma is typical case. However, MRI images showed no abnormal findings in our case. As a reason for that, we speculate that the optic nerve lesion is probably still localized in the optic disc, because of very early stage of infiltration from VRL. Moreover, past report described that not all cases have abnormal findings on MRI [12]. Therefore, clinicians should be aware of the potential limitations of MRI in detecting early-stage optic nerve lymphoma and rely on a comprehensive evaluation of findings from multiple diagnostic modalities.

In conclusion, our exploration into the progression of intraretinal and sub-RPE lesions to ION via OCT substantiates the lesions as forerunners of optic nerve infiltration by VRL. Despite significant therapeutic advancements, the persistence of hyperreflective deposits in the intraretinal and sub-RPE layers after treatment underscores the necessity for continuous monitoring. OCT’s indispensable role in differentiating optic neuropathy and the potential CNS spread from VRL necessitate vigilant observation and frequent evaluations to preemptively address any disease advancement, thereby emphasizing the importance of an integrated and proactive diagnostic and management strategy in suspected VRL cases.

Abbreviations

VRL

Vitreoretinal lymphoma

ION

Infiltrative optic neuropathy

CNS

Central nervous system

RPE

Retinal pigment epithelial

OCT

Optical coherence tomography

VO

Vitreous opacification

MRI

Magnetic resonance imaging

Author contributions

T.K. and S.K. participated in drafting the manuscript and collection, analysis, and interpretation of the data. S.K. and K.M. participated in diagnosis and treatment of the patient, drafting the manuscript, and revising the manuscript. S.F., T.F., Y.K., H.S., T.M. and K.N. critically reviewed the manuscript and reviewed the literature. All authors consented to their names being published in this report and insist on the intellectual honesty and validity of the data provided. All authors read and approved the final version of the paper.

Funding

No funding or grant support.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Written informed consent was obtained from the patient for publication of this case report and all accompanying images. A copy of the consent form is kept at our facility.

Competing interests

The authors declare no competing interests.