Bilateral optic disc edema and serous retinal detachment as initial ocular manifestations of systemic lymphoma: A case report and literature review

Abstract

This report describes a unique case of systemic diffuse large B-cell lymphoma (DLBCL) with initial ocular manifestations of bilateral optic disc edema and serous retinal detachment (SRD). A 29-year-old man presented with altered color vision in the left eye, mild fever, weakness, and headache, followed by bilaterally reduced visual acuity. Anterior segment and vitreous examinations showed no inflammation with sluggish response of light reflex. His fundus examination revealed bilateral multiple SRDs and optic disc swelling with choroidal thickening. On fluorescein angiography, pinpoint hyperfluorescence, associated dye pooling, and optic disc staining with leakage were found bilaterally. Laboratory studies revealed elevated C-reactive protein and mild leukocytosis with neutrophil predominance. He was provisionally diagnosed with probable Vogt-Koyanagi-Harada syndrome and received methylprednisolone pulse therapy. Five days later, his systemic condition deteriorated following initial ocular symptom improvement. Whole-body computerized tomography revealed clustered lymphadenopathies, which were interpreted as DLBCL after lymph node biopsy. His ocular condition improved after DLBCL chemotherapy. We hope to promote early recognition with appropriate workups through this case and literature review.

Introduction

Diffuse large B-cell lymphoma (DLBCL), which belongs to aggressive but potentially curable malignancies, is the most common type of non-Hodgkin lymphoma (NHL) and typically affects middle-aged or older adults. A case series reported DLBCL as the main intraocular lymphoma (IOL) subset in primary vitreoretinal lymphoma (91%) and systemic metastatic retinal lymphoma (83%).[1] Ocular findings of IOL are diverse, including anterior chamber reaction, vitreous inflammation, and vascular, retinal, or choroidal involvement, such as vasculitis, subretinal, and choroidal infiltration, possibly accompanied by optic disc swelling.

However, systemic lymphoma can present with an expanding spectrum of ocular manifestations as a masquerader rather than with the common presentations of IOL, making an accurate diagnosis a greater challenge.[2,3,4,5,6,7,8] The mechanism may be related to hematopoietic cancer characteristics, contributing to the hematogenous spread and infiltration of the choroid by tumor cells, which may lead to hematologic malignancy-associated serous retinal detachment (SRD).[6] On the other hand, the paraneoplastic response or primarily intravascular lymphomatous involvement is also postulated as a possible mechanism for various ocular presentations in patients with systemic lymphoma.[6] We aim to describe a young adult eventually diagnosed with systemic DLBCL, who initially presented with bilateral SRD and swollen optic nerve head.

Case Report

The patient was a 29-year-old frail-looking Taiwanese man who initially noted bilateral eyelid swelling after 3 days of oral cyclobenzaprine for his low back pain. His puffy eyelids improved after using a topical antihistamine agent and the withdrawal of cyclobenzaprine. However, he presented with decreased color sensation in the left eye and bilateral blurred vision 4 days later, accompanied by low-grade fever, weakness, and headache, but without neck stiffness. He was generally healthy before and denied having specific ocular or medical histories; his family history was unremarkable. The patient’s best-corrected visual acuity (BCVA) declined from 20/20 bilaterally to 20/25 and 20/40 in the right and left eyes, respectively. Both eyes had normal intraocular pressure, quiet anterior chamber, and clear vitreous cavity. Light reflex examinations revealed a sluggish response without relative afferent pupillary defect in both eyes. The Ishihara color plate examination showed 15/15 in both eyes, but the patient subjectively reported a gloomier color sense in the left eye than in the right eye. His retinal examination showed bilateral optic disc swelling and multifocal subretinal fluid [Figure 1a and b], and optical coherence tomography (OCT) of the macula revealed choroidal thickening and macular subretinal fluid with central subfield thickness of 244 and 358 μm in the right eye and left eye, respectively [Figure 1c and d], and optic nerve head edema [Figure 1e-h] in both eyes.

Figure 1.

Color fundus photographs of the right eye (a) and left eye (b) revealed multifocal serous retinal detachments, optic disk swelling, choroidal folds, and retinal vascular tortuosity. OCT showed choroidal thickening and macular subretinal fluid in the right and left eyes (c and d, respectively). Extracted vertical tomogram of optic nerve head edema by OCT of the right eye (e and g) and left eye (f and h) demonstrated bilateral marked thickening of RNFL with measurements of RNFL well above normal range for age (green area). OCT: Optical coherence tomography, RNFL: Retinal nerve fiber layer

The patient underwent fluorescein angiography (FA) examination, demonstrating pinpoint hyperfluorescence from the early to late phase [Figure 2a and b], followed by multilobular dye pooling in the subretinal space, and optic disc leakage in both eyes in the late phase [Figure 2c and d]. The visual evoked potentials revealed bilateral optic nerve dysfunction [Figure 3]. Magnetic resonance imaging demonstrated no organic lesions in the brain or eyes. Laboratory studies revealed mild leukocytosis (9800/μl), neutrophil predominance (81.8%), and elevated C-reactive protein (90.7 mg/l) with unremarkable results of erythrocyte sedimentation rate. The serological tests for detailed autoimmune and infection profiles were all negative. A diagnosis of probable Vogt-Koyanagi-Harada (VKH) syndrome was made according to bilateral SRD and swollen optic disc without evidence of other ocular diseases, trauma, or surgery. He received a 3-day course of methylprednisolone pulse therapy at 1 g/day, followed by oral cyclosporine 150 mg with prednisolone 30 mg/day, and ocular symptoms, as well as headache, improved.

Figure 2.

The early phase of the FA showed pinpoint hyperfluorescence with leakage in the right eye (a) and left eye (b). Dye pooling in multiple subretinal spaces in the late phase of FA as well as optic disc staining with leakage in the right and left eyes (c and d, respectively). FA: Fluorescein angiography

Figure 3.

The visual evoked potentials revealed prolonged latencies of bilateral P100 wave as 122 ms with a greater reduction of P100 wave amplitude in the left eye compared to the right eye

Five days later, he had an episode of fever and dyspnea with bilaterally increased pulmonary infiltration on the chest X-ray, followed by respiratory distress. Septic workups, including bronchial washing, were performed, but yielded no conclusive results. Given the atypical course, whole-body computerized tomography was arranged, and abnormal bilateral clustered lymphadenopathies in the neck were found. The right neck lymph node biopsy showed the histologic diagnosis of DLBCL based on diffuse infiltrates of medium-to-large-sized atypical lymphoid cells positive for CD20 with nuclear pleomorphism and frequent apoptosis. The patient was then diagnosed with DLBCL stage IV, which most likely involved the lungs and bone marrow. Chemotherapy regimens with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) were started accordingly, and DLBCL subsequently stabilized. Resolution of optic disc swelling and SRD in both eyes was noted [Figure 4] during the chemotherapy, concurrently with stable systemic condition and the improvement of BCVA to 20/20 and 20/25 in the right eye and left eye, respectively, after a 3-month follow-up period. The concise disease course of this patient is depicted in the clinical timeline [Figure 5].

Figure 4.

The follow-up multimodal imaging three months after the initial presentation presented as follows. Color fundus photographs showed resolution of serous retinal detachments in the right eye (a) and left eye (b) with no optic disc swelling. Optical coherence tomography revealed no subretinal fluid in the right and left eyes (c and d, respectively), and demonstrated resolution of optic nerve head edema in the right eye (e) and left eye (f) with bilateral retinal nerve fiber layer thickness returning to the normal range (g)

Figure 5.

Clinical timeline: 29-year-old Taiwanese male was eventually diagnosed as systemic diffuse large B-cell lymphoma with initial ocular manifestations of optic disc edema and multifocal serous retinal detachment. BCVA: Best-corrected visual acuity, DLBCL: diffuse large B-cell lymphoma, FA: Fluorescein angiography, LAP: Lymphadenopathy, MRI: Magnetic resonance imaging, MTP; Methylprednisolone, ODE: Optic disc edema, R-CHOP: Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, SRD: Serous retinal detachment, VEP: Visual evoked potential, VKH: Vogt-Koyanagi-Harada syndrome, WBCT: Whole-body computed tomography

Discussion

This report stresses that the ocular manifestations mimicking VKH may be substantially associated with systemic lymphoma. Compared with typical signs of IOL, our case presents several features of VKH: a suspicious prodromal stage, binocular involvement, multifocal SRD with pinpoint hyperfluorescence on FA, choroidal thickening, optic disc swelling, and hyperemia. Of note, the absence of an anterior chamber reaction and vitritis is the main unusual characteristic of VKH in our case. Any unexplained atypical sign in the display of VKH warrants further consideration of other diagnoses.[2,6] As Moussa et al. mentioned, no evidence of other inflammatory signs and an absence of optic disc hyperemia helped raise the suspicion of other diagnoses in a patient with the tentative diagnosis of VKH.[6] By contrast, we propose the possibility of masquerade syndromes in patients with typical features of VKH, even with optic disc swelling and hyperemia. It is also essential for patients with human immunodeficiency virus reactivity to receive more detailed systemic surveys in newly diagnosed VKH due to their immunosuppression, cytokine dysregulation status, and the higher risk of NHL.[2,5]

Typical patterns of acute VKH on FA are known for delayed choroidal filling in the early phase, a classic “starry sky” appearance of the pinpoint hyperfluorescent leakage, dye pooling in the subretinal space in the late phase, and optic disc staining with leakage. A ”hot disc” appearance was observed in 94.4% of patients with acute VKHD by Arellanes-García et al.[9] These relevant features prompted us make the diagnosis of VKH. In hindsight, the FA finding of systemic lymphoma can vary in patients and mimic similarly presenting conditions like VKH, even if the apparent optic disc leakage existed. The importance of FA findings in leukemia was also emphasized by some authors, especially the hyperfluorescent pinpoints, which may be caused by the accumulation of leukemic cells leading to choriocapillaris ischemia and the disruptions of intercellular tight junctions at the retinal pigment epithelium level.[10,11] Different pinpoint hyperfluorescent patterns can be helpful in the differential diagnosis.[10,11,12,13] Stippled pinpoint hyperfluorescence without fluorescence pooling and bilateral disc staining, which may be deep retinal punctiform and hyperfluorescent infiltrates, should not be directly presumed as VKH features.[12]

In addition to ophthalmic examinations, detailed systemic reviews and comprehensive laboratory studies can help raise suspicion for differentiating neoplastic masquerade syndromes, especially in the population with frail appearances and unusual demographic data. Moreover, the declined visual acuity was thought to be due to both maculopathy and optic neuropathy as OCT of the macula revealed multilobular subretinal fluid in both eyes and color sense decreasing was found in the left eye as well as the increased retinal nerve fiber layer thickness in the OCT of optic nerve head (optic disc edema) with sluggish direct light reflex in both eyes. In this case, we thought that both optic neuropathy and maculopathy could be due to subretinal serous detachment which could result from the infiltration of hematological cancer cells as mentioned in the introduction part. Concerning hematological neoplasms, whole and differential blood counts are the most common laboratory studies performed for patients with lymphoma, but they may show normal values in the early stage. Marked elevation of serum soluble interleukin-2 receptor (sIL-2R) and lactate dehydrogenase (LDH) may also contribute to the screening and early recognition of a masquerade syndrome in malignant lymphoma after other false-positive conditions are excluded.[14,15] Compared to normal level of sIL-2R in serum of patient with VKH,[16] the multivariate analysis from the study of Murakami et al. strongly suggested the higher diagnostic accuracy for lymphomas based on combined age >46 years, LDH >173 U/l, and a sIL-2R cutoff value at 1946 U/ml with the area under the curve reaching 0.733.[15]

The treatment response to the diagnosis expedited the pursuit of other diagnoses. The temporary improvement of ophthalmic manifestations from pulse therapy of the corticosteroid had led to systemic exacerbations of the so-called “tumor lysis syndromes,” which tends to develop in large tumor burdens and/or tumors with rapidly dividing cells like lymphoma, as the steroid reached a partial therapeutic rather than cytotoxic effect and resulted in the release of tumor cell contents and cytokines into the bloodstream. We can learn from this case that DLBCL could also present as optic disc edema and exudative or SRDs. Furthermore, choroidal thickening and further workup ultimately resulted in a correct diagnosis, appropriate treatments, and also the fair outcomes ophthalmologically as well as systemically.

The main limitation of our case is the absence of ocular fluid or chorioretinal cytopathologic examination, making the possibility of an IOL a mystery. We attribute these VKH-like ophthalmic manifestations to systemic DLBCL, according to the improvement of ocular involvement after the chemotherapy. Furthermore, we lack laboratory data for LDH and sILR-2R as initial screening tools. Hopefully, based on the sharing of our case and the literature review, this could lead medical societies toward early recognition of systemic lymphoma in the future with appropriate workups and interventions accordingly.

Conclusion

We highlight the potential of systemic lymphoma presenting with the initial ocular manifestations of VKH-like bilateral optic disc swelling and SRD. Comprehensive ophthalmic examinations with careful interpretations of multimodal imaging and laboratory investigations, such as LDH and sILR-2R, can be useful in the early recognition of masquerade syndromes, particularly regarding hematological neoplasms. A timely reevaluation must be performed if the patient fails to respond to the treatment of the relevant diagnosis.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that his name and initials will not be published, and due efforts will be made to conceal his identity.

Data availability statement

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Financial support and sponsorship

Nil.

Conflicts of interest

Dr. Ju-Chuan Yen and Dr. Shiow-Wen Liou, the editorial board members at Taiwan Journal of Ophthalmology, had no roles in the peer review process of or decision to publish this article. The other authors declared no conflicts of interest in writing this paper.