Hyperviscosity Retinopathy Due to Waldenström Macroglobulinemia: A Case Report and Literature Review

Abstract

Purpose:

This case report describes a case of hyperviscosity retinopathy secondary to the rare systemic hematologic malignant neoplasm Waldenström macroglobulinemia.

Methods:

Fundus photography, fluorescein angiography, optical coherence tomography (OCT), and OCT angiography were used as imaging modalities to characterize this pathology.

Results:

A 51-year-old man presented with hyperviscosity retinopathy and uniquely angiographically silent serous macular detachment. Over a 6-month period, he was treated with systemic and local therapies with little improvement in the hyperviscosity retinopathy, serous macular detachments, or visual acuity.

Conclusions:

Hyperviscosity retinopathy secondary to Waldenström macroglobulinemia presents a challenge to treating ophthalmologists given its rarity and the range of treatment responses described in the literature. Our patient’s lack of response to antivascular endothelial growth factor and normal findings in OCT angiography and fluorescein angiography suggested the mechanism of subretinal fluid accumulation was not vascular endothelial growth factor mediated. Visual prognosis was guarded.

Introduction

A rare disease, Waldenström macroglobulinemia (WM) is a lymphoplasmacytic lymphoma characterized by malignant B cells with accompanying accumulation of immunoglobulin M (IgM) monoclonal proteins in the blood. ¹ Patients are often asymptomatic but can present with constitutional symptoms, hyperviscosity syndrome, anemia and lymphopenia, and vascular disturbances. ² Ocular symptoms of blurry or loss of vision are thought to be a manifestation of hyperviscosity syndrome. Retinal manifestations include retinal vein engorgement and vessel tortuosity, scattered hemorrhages and microaneurysms, optic disc edema, and venous beading. ^{3 –6} We present a case of retinopathy secondary to WM, its characteristic imaging, and its treatment.

Methods

Case Report

A 51-year-old African American man with no significant ocular history was seen in consultation for a 1-month history of gradual-onset blurred vision. Associated symptoms of vertigo, epistaxis, and hearing loss were noticed prior to the onset of vision loss. He was admitted for anemia that required multiple blood transfusions and was diagnosed with WM after extensive workup. On examination, visual acuity (VA) measured 20/200 OD and 20/40 OS. He had normal intraocular pressures, no relative afferent pupillary defect, and no motility or visual field deficits.

Findings from the anterior segment examination were normal, and the dilated fundus examination showed exudation, retinal hemorrhages, and significant vascular dilation and tortuosity (Figure 1). Fluorescein angiography revealed normal filling with no appreciated delay in arteriovenous transit time and late leakage of retinal veins, including the macula, with blockage in the periphery corresponding to retinal hemorrhages (Figure 2). Optical coherence tomography (OCT) demonstrated serous macular detachment with intraretinal fluid in both eyes (Figure 3). OCT angiography (OCTA) demonstrated no abnormalities of retinal or choroidal vasculature (Figure 4). During the admission, the patient received plasma exchange and bendamustine chemotherapy per hematology-oncology recommendations and was discharged to continue outpatient therapy.

Figure 1.

Fundus photograph of the (A) right and (B) left eyes demonstrating numerous midperipheral intraretinal/subretinal hemorrhages, perivascular exudation, and pockets of subretinal fluid.

Figure 2.

Fluorescein angiography of the (A) right and (B) left eyes showing scattered punctate areas of hyperfluorescence in the midperiphery and late leakage of retinal veins with (C) blockage in the periphery corresponding to retinal hemorrhages.

Figure 3.

Optical coherence tomography of the (A) right and (B) left eyes on presentation to the clinic showing bilateral subretinal and intraretinal fluid.

Figure 4.

Optical coherence tomography angiography of the left eye showing no perfusion defects at the (A) superficial retinal and (B) deep retinal circulations, (C) avascular layer, or (D) choriocapillaris level.

Results

Given the significant subretinal and intraretinal fluid, the patient was offered intravitreal bevacizumab treatment in the right eye 15 days after initial presentation. He returned 1 month later revealing a VA decline to 20/200 OD and 20/40-2 OS with mild improvement in retinal hemorrhages in both eyes on his fundus examination but without significant changes on his OCT imaging. He was again treated with intravitreal bevacizumab in the right eye. The patient was lost to follow-up for 4 months. On return to the clinic, his VA was stable at 20/200 OD and improved to 20/30 OS. Fundus examination revealed markedly decreased retinal hemorrhages (Figure 5). OCT demonstrated stable subretinal fluid in the right eye with resolution of subretinal fluid in the left eye (Figure 6). In summary, the patient had 4 visits and received 2 intravitreal bevacizumab injections within a 5-month period. Given the patient’s phakic status and the potential for accelerated cataract formation, intravitreal steroids were avoided.

Figure 5.

Fundus photographs of the (A) right and (B) left eyes 4 months after initial presentation demonstrating improved midperipheral retinal hemorrhages, perivascular exudation, and subretinal fluid.

Figure 6.

Optical coherence tomography of the (A) right and (B) left eyes 4 months after initial presentation revealing stable subretinal fluid and resolved subretinal fluid, respectively.

Conclusions

Our case illustrates the many retinal manifestations of hyperviscosity syndrome secondary to WM. Bilateral central retinal vein occlusion has also been reported as a possible, although uncommon, presenting feature of WM. ^7,8 The proposed pathophysiology of hyperviscosity retinopathy is vaso-occlusive, with increased concentration of macroglobulins leading to decreased blood flow to the retina, subsequent rise in intravascular pressure, and resulting clinical findings of retinal venous obstruction. ⁹ These fundoscopic abnormalities, seen in 30% to 40% of patients with WM, typically manifest at a threshold serum viscosity. ^1,3,9 Several other conditions may lead to hyperviscosity syndromes with similar retinal findings, including multiple myeloma, cryoglobulinemia, disseminated intravascular coagulation, thrombotic thrombocytopenic purpura, and preeclampsia/eclampsia/HELLP (hemolysis, elevated liver enzymes, and low platelet count occurring in association with preeclampsia). ¹⁰

Our patient presented with a rare ocular manifestation of serous macular detachment with absence of angiographic leakage, or angiographically “silent macula,” which has been previously described. ^4,9,11 Although fundus findings in patients with hyperviscosity syndrome secondary to WM mimic that of a central retinal vein occlusion, hemodynamic studies have shown no abnormalities in patients with WM. ¹² OCTA findings of normal retinal and choroidal vasculature in this case also confirmed that the intraretinal fluid and subretinal fluid were not a result of an ischemic process.

These serous retinal detachments are hypothesized to be secondary to IgM accumulation in the subretinal space, creating an osmotic gradient and subsequent fluid shift, although the pathophysiology is debated. ^1,13 Another hypothesis, attributed to Gass, ¹⁴ for serous retinal detachment formation is that deposition of immune complexes in the choriocapillaris lead to localized overlying retinal pigment epithelium atrophy and malfunction of the retinal pigment epithelium pump. This then leads to subretinal serous fluid accumulation, ¹⁴ similar to mitogen-activated protein kinase inhibitor–induced maculopathy. ⁷ Indocyanine green angiography has been reported to have normal findings in this condition, confirming that the choroid is not the source of the fluid. However, this imaging modality would unlikely reflect immune complex deposition at the level of the capillaris.

Diagnosis of WM is made by presence of IgM monoclonal gammopathy and characteristic bone marrow biopsy findings. Although there is no cure, treatment includes plasmapheresis, chemotherapy, and other targeted therapies. ¹⁵ Patient response to these treatment modalities is highly variable. Hyperviscosity retinopathy seems most responsive to systemic treatments that rapidly lower IgM levels and serum viscosity, such as plasmapheresis and plasma exchange, in conjunction with systemic chemotherapy to prevent paraprotein production. ^6,16 In some reports, patients with serous macular detachments have improvement or even resolution of serous macular detachment with systemic therapy alone. ^{6 –8} The addition of local treatment with intravitreal injections of steroids and antivascular endothelial growth factor (anti-VEGF) therapy has also had mixed results, with some case reports demonstrating resolution of serous macular detachment, although the time for improvement varies from weeks to months. ^5,13,16,17 Xu et al found that intravitreal bevacizumab therapy resulted in reduction of intraretinal fluid but no significant change in subretinal fluid. ⁵

Our patient demonstrated nominal improvement in VA and subretinal fluid with use of intravitreal anti-VEGF agents and systemic treatments. The lack of response to anti-VEGF as well as normal OCTA and fluorescein angiography findings suggested that the mechanism of fluid accumulation was not VEGF mediated.

However, improvement of the hyperviscosity retinopathy or serous macular detachment does not necessarily correlate with improvement in VA, as demonstrated by inconsistent improvement in VA across case reports. Visual prognosis is guarded, with some cases demonstrating improvement with systemic therapy alone ^6,8 or with a combination of systemic and local treatment, some remaining stable, and some showing no improvement at all. ^5,13,16,17 Given the range of treatment responses described in the literature, there are insufficient data for an established treatment protocol for retinopathy secondary to WM. Further research is necessary to improve visual outcomes for patients with hyperviscosity retinopathy.