Bilateral Choroidal Infiltrates as the Initial Manifestation of Waldenström Macroglobulinemia Relapse

Abstract

Purpose:

This work describes a case of Waldenström macroglobulinemia (WM) relapse presenting with unilateral blurred vision.

Method:

A case report is presented.

Results:

A 60-year-old woman with a history of WM in remission was referred for suspicious peripheral choroidal lesions and left optic disc swelling. Magnetic resonance imaging revealed optic nerve and cranial nerve infiltration consistent with central nervous system invasion from WM relapse, called Bing-Neel syndrome. Irradiation of the optic nerve and systemic targeted therapy were successful in addressing the ocular features as well as reducing immunoglobulin M paraprotein levels and lymphoproliferative disease burden.

Conclusions:

We described the first documented case to our knowledge of intraocular involvement as the earliest sign of relapse of WM. Ophthalmology assessment is warranted in patients with a history of WM who present with new ocular symptoms to aid early detection and treatment of this disease.

Introduction

Waldenström macroglobulinemia (WM) (also known as lymphoplasmacytic lymphoma) is an indolent form of non-Hodgkin lymphoma. The disease is characterized by overproduction of immunoglobulin M (IgM) from abnormal lymphocytes and plasma cells, leading to blood hyperviscosity and bone marrow and lymph node infiltration. Clinical features include nonspecific B symptoms, hepatosplenomegaly, and lymphadenopathy. An extremely rare complication of WM, occurring in 1 in 100 cases of WM, is Bing-Neel syndrome (BNS), which was first described in 1936 by Jens Bing and Axel Valdemar Neel. ¹ This is characterized by infiltration of abnormal lymphocytes and plasma cells into the central nervous system (CNS). Orbital infiltration of this disease is rarely described in the literature, and there are no reported cases of intraocular involvement. In this report, we describe the first case to our knowledge in which ocular symptoms and intraocular features on fundus examination have been the initial manifestation of systemic WM relapse.

Methods

Case Report

A 60-year-old woman was referred to an ophthalmologist for evaluation of bilateral peripheral fundus lesions, left optic disc swelling, and 3 months of blurred vision in the left eye. Her ocular history was unremarkable, and she was otherwise well with no symptoms suggestive of underlying inflammatory disease or infection. Her medical history was significant for WM, which initially progressed from IgM monoclonal gammopathy of undetermined significance. She had received bendamustine and rituximab immunochemotherapy and was in remission and off treatment for the past 3 years. Coinciding with the onset of ocular symptoms, it was noted during a routine hematology consultation that her IgM paraprotein level had increased from 0.9 g/dL to 1.8 g/dL over a period of 12 months. Because results from her full blood count and red blood cell (RBC) morphology were normal and she remained clinically well with no B symptoms, palpable lymphadenopathy, or hepatosplenomegaly, an initial decision was made for closer follow-up with a monitoring schedule of every 3 months instead of immediate salvage therapy.

On initial examination, her best-corrected visual acuity was 20/20 in both eyes with normal intraocular pressures. Pupils were equal in size and briskly reactive. The anterior segment examination of both eyes had unremarkable findings, with visually insignificant cataracts and no anterior chamber inflammation. Dilated fundus examination revealed left optic disc swelling with marked bilateral chorioretinal infiltrates that were more prolific in the left eye compared with the right eye. Fundus autofluorescence demonstrated left optic disc swelling, unremarkable fovea and retinal vessels, and some nonspecific areas of hypoautofluorescence. Spectral-domain optical coherence tomography (OCT) revealed no retinal abnormalities. Enhanced-depth imaging was not performed. A specific cross-sectional slice through the lesions in the left eye did not show retinal abnormalities, suggesting that the lesions were confined to the choroid (Figure 1).

Figure 1.

Imaging at initial presentation. (A) Color fundus photographs disclose bilateral, symmetrical infiltrates of the choroid that were worse in the left eye compared with the right eye. There is swelling of the left optic disc. (B) Fundus autofluorescence demonstrates nonspecific areas of hypoautofluorescence, a swollen left optic disc, unremarkable fovea, and normal caliber of the retinal vessels. (C) Spectral-domain optical coherence tomography, including specific cross-sectional slices through the lesions, shows no retinal abnormalities, suggesting that the lesions were confined to the choroid.

Magnetic resonance imaging (MRI) of the brain and orbits showed diffuse infiltration, thickening, and enhancement of the left optic nerve extending approximately 3.2 cm within the intraorbital segment, the optic canal, and prechiasmal segment. There was also peripheral enhancement seen around the right optic nerve, as well as along the bilateral fifth cranial nerves, the oculomotor nerves, and the lower cranial nerves within the internal acoustic meatus (Figure 2).

Figure 2.

Axial views of gadolinium-enhanced, T1-weighted magnetic resonance imaging of the brain and orbits show a diffusely infiltrated, thickened, and enhanced left optic nerve that extends approximately 3.2 cm within the intraorbital segment, the optic canal, and prechiasmal segment. Peripheral enhancement is also seen around (A) the right optic nerve as well as (B) along the oculomotor nerves, (C) the trigeminal nerves, and (D) the lower cranial nerves within the internal acoustic meatus.

Results from a second full blood count and RBC morphology were normal. IgM paraprotein level was 2.0 g/dL. Cerebrospinal fluid (CSF) was clear with no evidence of abnormal lymphocytes or plasma cells. Further imaging was arranged, including a staging computed tomography (CT) scan and positron emission tomography scan, that identified systemic progression of nodal and extranodal disease above and below the diaphragm. A mesenteric lymph node biopsy showed histological features of WM relapse without evidence of transformation (Figure 3).

Figure 3.

Results of blood tests and further investigations performed in response to the suspicious ocular features. A decision to treat was made following multidisciplinary discussion. Abdo indicates abdomen; CSF, cerebrospinal fluid; CT, computed tomography; FDG, fluorine-18 fluoro-2-deoxy-D-glucose; IgM, immunoglobulin M; LN, lymph node; PET, positron emission tomography; RBC, red blood cell.

The patient received 2-Gy radiotherapy to the left optic nerve and commenced a trial therapeutic agent, TG-1701, which is an oral, once-daily Bruton tyrosine kinase inhibitor. After 1 monthly cycle of treatment, her vision had subjectively improved, and she had minor response reduction in her IgM paraprotein level to 1.4 g/dL. After 2 months of treatment, there was a further reduction in her paraprotein level to 1.1 g/dL and lymph node mass reduction on a second CT scan consistent with minor response. After her sixth cycle, she had partial response to treatment with further lymph node mass reduction on interval CT imaging as well as a reduction in her paraprotein level to 0.9 g/dL. After 12 monthly cycles of treatment, her paraprotein level was 0.5 g/dL. A formal ophthalmic assessment at the time showed that her ocular symptoms had resolved. Her disc swelling had resolved, both clinically and on nerve fiber layer OCT. Dilated fundus examination demonstrated residual multifocal choroidal infiltrates. The posttreatment OCT was similar in appearance to the original images (Figure 4).

Figure 4.

Imaging after 12 months of treatment. (A) Color fundus photographs show resolution of disc swelling and residual multifocal choroidal infiltrates. (B) Posttreatment line scans from the macular cube optical coherence tomography show similar appearance to the original images.

Results

This was the first published case to our knowledge of blurred vision, optic disc swelling, and choroidal infiltrates as the initial manifestation of WM relapse. The authors believe that this was also a case of BNS, an extremely rare complication of WM, in which malignant lymphoplasmacytic cells invade the CNS. The criterion standard for diagnosis of BNS is a histological biopsy of the CNS that demonstrates lymphoplasmacytic lymphoma and CSF analysis that identifies leptomeningeal spread. ² A tissue diagnosis was not obtained because biopsy of the optic nerve or other cranial nerves was deemed too risky. Additionally, in this case no abnormal lymphoplasma cells were seen on CSF analysis. Nonetheless, the MRI findings were suggestive of CNS infiltration, and this led to further staging imaging and lymph node biopsy, which confirmed WM relapse.

Limited information is available on BNS. The largest retrospective review by Simon et al identified 44 French patients treated for BNS across 17 centers. ³ Castillo and colleagues identified 34 patients with BNS from 8 centers across the United States and Europe. ⁴ The median age at diagnosis was 63 and 62 years, respectively. Males comprised 80% and 56%, respectively. Symptoms and signs included balance/gait disturbance (12%-48%), altered mental status (27%-35%), cranial nerve palsy (29%-36%), and blurred vision (15%), with no reports of intraocular involvement. All patients received a combination of MRI, CSF sampling, and tissue biopsy to aid the diagnosis.

Both studies lacked uniformity on treatment approaches. A range of therapeutic options have been used with an overall response rate of 70% to first-line therapy; however, no differences according to the type of treatment could be made. Several case reports have supported ibrutinib as first-line chemotherapy, which has been proven to penetrate the CNS. ^5,6 The patient in the present case received radiotherapy and responded to TG-1701, a second-generation Bruton tyrosine kinase inhibitor, with improvement in ocular symptoms and reduction in paraprotein levels as well as lymph node mass size after only 1 monthly cycle of treatment.

Conclusions

This report adds to the existing literature, providing an atypical presentation of BNS with intraocular involvement and normal CSF. To the best of our knowledge, this is the first documented case of intraocular involvement as the initial clinical sign of relapse of WM. Normal findings from a full blood count and RBC morphology, as well as the lack of B symptoms or clinically evident lymphadenopathy or hepatosplenomegaly, may not be sufficient to exclude relapsing disease. Ophthalmology assessment is warranted in patients with a history of WM who present with new ocular symptoms, particularly in partients with concurrent rising IgM paraprotein levels, to aid early detection and treatment of this disease.