Hyperviscosity-Related Retinopathy and Serous Macular Detachment in Waldenstrӧm Macroglobulinemia Managed With Zanubrutinib

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doi:10.62055/31886630Xe

ABSTRACT 

Background

Waldenstrom macroglobulinemia (WM) is an uncommon lymphoproliferative B-cell disorder characterized by overproduction of monoclonal immunoglobulin type M (IgM) paraprotein, which can result in a hyperviscosity syndrome with ocular manifestations. Signs of hyperviscosity-related retinopathy include intraretinal hemorrhages, vascular dilation and tortuosity, optic disc edema, and rarely, serous macular detachments (SMD). When eye care clinicians suspect hyperviscosity-related retinopathy, an urgent hematology consultation is necessary as treatment for WM frequently includes plasma exchange or plasmapheresis and chemotherapy.

CASE REPORT

A 63-year-old African American male presented with blurred vision in both eyes for approximately the last 10 days. Notable exam findings at presentation included hyperviscosity-related retinopathy signs of bilateral dilated and tortuous retinal veins, significant intraretinal hemorrhages with Roth spots, hyperemic and elevated optic nerves without blurred margins and macular edema with SMD. Additionally, at onset of the visual symptoms, the patient was found to have malignant hypertension, normocytic anemia, thrombocytopenia, and marked rouleaux formation seen on peripheral blood smear. The patient was co-managed with a retinal ophthalmologist and hematologist. An elevated IgM of 10,640 mg/dL and bone marrow biopsy confirmed a diagnosis of lymphoplasmacytic lymphoma with WM. The patient was treated with plasma exchange and chemotherapy, including zanubrutinib, a Bruton’s tyrosine kinase inhibitor. Over an 8-month follow-up period, the hyperviscosity-related retinopathy significantly improved while the SMD decreased minimally.

CONCLUSION

Hyperviscosity-related retinopathy with SMD warrants a prompt hematology evaluation for WM. Systemic treatment of plasma exchange and chemotherapy for WM may improve signs of retinopathy and SMD. However, recovery of visual acuity is generally incomplete due to persistent subretinal fluid associated with the SMD, as seen in this case.

Keywords: Waldenstrom macroglobulinemia, hyperviscosity-related retinopathy, hyperviscosity syndrome, serous macular detachment, zanubrutinib

INTRODUCTION

Waldenstrom macroglobulinemia (WM) is an uncommon lymphoproliferative B-cell disorder characterized by overproduction of monoclonal immunoglobulin type M (IgM) paraprotein, which can increase the blood viscosity resulting in a hyperviscosity syndrome.¹ Hyperviscosity syndrome may manifest initially with neurological deficits, spontaneous bleeding from mucous membranes, cardiorespiratory distress, and/or visual changes.² Hyperviscosity-related retinopathy has been reported in 34% to 56% of patients with WM at diagnosis and consists of intraretinal hemorrhages, vascular dilation and tortuosity, and optic disc edema.^3-5 In addition, a serous macular detachment (SMD) rarely develops in patients with WM, yet when present, often results in a moderate reduction in vision and limited visual recovery.^5,6

CASE REPORT

A 63-year-old African American male presented with blurred vision in both eyes for approximately the last 10 days. He further reported he was evaluated by an eyecare provider at a different practice, 7 days earlier, who found “swelling in his retina” with malignant hypertension and was sent to the local emergency department for management. The patient was hospitalized for 3 days to control his hypertension and upon discharge was advised to follow-up with a hematologist due to additional findings of normocytic anemia, thrombocytopenia and marked rouleaux formation seen on peripheral smear. His ocular history was unremarkable and he wore glasses only for near work. His medical history included the recent diagnosis of hypertension treated with lisinopril-hydrochlorothiazide for the last 7 days.

Best-corrected visual acuity was 20/40 in each eye. Extraocular muscle motility was full without restrictions, confrontation fields were full, and pupils were equal, round, reactive to light with no afferent pupillary defect in both eyes. Anterior segment findings were unremarkable, and intraocular pressures were 18 mmHg in both eyes via Goldmann applanation tonometry. Dilated fundus examination revealed bilateral dilated and tortuous retinal veins, significant intraretinal hemorrhages with Roth spots, hyperemic and elevated optic nerves without blurred margins and macular edema (Figure 1 A, B). OCT displayed bilateral intraretinal edema centrally and greater nasally, subretinal fluid associated with SMD, focal outer retinal disruption at the peak of the SMD in the right eye, and central subfield thickness of 827 µm in the right eye and 807 µm in the left eye (Figure 2 A, B).

Figure 1. Color fundus photography of both eyes over 8 months. (A, B) At initial presentation showing hyperviscosity-related retinopathy signs of dilated and tortuous retinal veins, significant intraretinal hemorrhages with Roth spots, hyperemic and elevated optic nerves without blurred margins and macular edema in the right and left eye.

Figure 2. Spectral-domain optical coherence tomography macular B-scan imaging of both eyes over 8 months. (A) Right eye, at initial presentation, showing intraretinal edema centrally and greater nasally, subretinal fluid with serous macular detachment, focal outer retinal disruption at the peak of the serous detachment, and central subfield thickness of 827 µm. (B) Left eye, at initial presentation, showing intraretinal edema centrally and greater nasally, subretinal fluid with serous macular detachment, and central subfield thickness of 807 µm.

Laboratory results available for review at the initial examination revealed low hemoglobin level of 8 g/dL, low platelet count of 109 K/mcL, and serum protein electrophoresis showed an abnormally high beta region. Blood pressure measured in the office was 149/89 mmHg. Based on clinical findings of hyperviscosity-related retinopathy, bilateral SMD, and abnormal laboratory findings, a hyperviscosity syndrome was suspected. The patient was referred to a retinal specialist to consider treatment for the macular edema and referred to a hematologist for further work-up of potential hyperviscosity syndrome with lymphoplasmacytic lymphoma or multiple myeloma.

Evaluation by the retinal specialist 3 days later concluded stable examination findings with a recommendation of treatment with intravitreal aflibercept given the significant macular edema; however, the patient refused at this visit and agreed to return in 2 weeks for treatment. At the following visit with the retinal specialist, increased macular edema was noted and blood pressure measured 184/125 mmHg. Intravitreal aflibercept was not performed; instead, the patient was referred to the local emergency department for management of the hypertensive emergency and evaluation with hematology.

Upon hospitalization, the patient’s blood pressure was normalized, and his medication was switched from lisinopril-hydrochlorothiazide to amlodipine. Hematology evaluation revealed an elevated serum IgM of 10,640 mg/dL and bone marrow biopsy with malignant B cells positive for the L265P mutation in the MYD88 gene, consistent with a diagnosis of hyperviscosity syndrome and lymphoplasmacytic lymphoma (LPL) with WM. Table 1 provides additional laboratory and pathology results. The patient underwent 5 rounds of plasma exchange over 5 days resulting in a decreased serum IgM of 3,960 mg/dL. Over the next 3 months, the patient completed 3 cycles of bendamustine and rituximab therapy, further decreasing the serum IgM to 1,880 mg/dL. Prior to the planned next cycle of chemotherapy, his serum IgM increased to 10,860 mg/dL. Concerning for disease progression at that time, he underwent 3 rounds of plasma exchange over the next 4 days, in which serum IgM decreased to 4,286 mg/dL, and he was started on zanubrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor. Over the next 5 months, serum IgM levels ranged from 4,721 mg/dL to 6,210 mg/dL and the patient continued zanubrutinib treatment without any further disease progression.

Since initiation of systemic treatment, the patient continued follow-up eye examinations monthly in which best-corrected visual acuity remained stable at 20/40 in both eyes. The retinal specialist determined intravitreal anti-VEGF injections were not recommended for the patient in the setting of WM due to lack of supportive evidence in the literature. It was hypothesized that the patient’s current chemotherapy management may aid in improvement of his hyperviscosity-related retinopathy. Three months after presentation, a mild improvement of the hyperviscosity-related retinopathy was noted in both eyes (Figure 1 C, D). OCT imaging revealed minimal improvement of intraretinal edema with a slight decrease in overall area and height of the SMD in both eyes (Figure 2 C, D). Eight months after presentation and five months after initiation of zanubrutinib, a significant improvement in the hyperviscosity-related retinopathy was seen in both eyes with scattered mid-peripheral retinal hemorrhages remaining (Figure 1 E, F). On OCT imaging of the right eye, the intraretinal edema further improved and the SMD area was slightly decreased (Figure 2E). The left eye showed a similar improvement of intraretinal edema and the SMD area and height mildly decreased (Figure 2F). Currently, the patient remains under regular follow-up with his hematologist for systemic treatment of LPL with WM and is co-managed monthly in the eye clinic.

Figure 1C, 1D. At 3 months after presentation revealing a mild improvement of hyperviscosity-related retinopathy in the right and left eye.

Figure 1C, 1D.  Right eye, at 3 months after presentation, showing minimal improvement of intraretinal edema with a slight decrease in overall area and height of serous detachment, and central subfield thickness of 708 µm. (D) Left eye, at 3 months after presentation, showing minimal improvement of intraretinal edema with a slight decrease in overall area and height of serous detachment, and central subfield thickness of 696 µm.

Figure 1E, 1F.  At 8 months after presentation and 5 months after initiation of zanubrutinib revealing a significant improvement in the hyperviscosity-related retinopathy with scattered mid-peripheral retinal hemorrhages remaining in the right and left eye.

Fig 2E, 2F.  (E) Right eye, at 8 months after presentation and 5 months after initiation of zanubrutinib, revealing further improvement of intraretinal edema, serous detachment area slightly decreased, and central subfield thickness of 645 µm. (F) Left eye, at 8 months after presentation and 5 months after initiation of zanubrutinib, revealing further improvement of intraretinal edema, serous detachment area and height mildly decreased, and central subfield thickness of 558 µm.

DISCUSSION

WM is an uncommon lymphoproliferative B-cell disorder characterized by elevated serum monoclonal IgM, with an annual incidence of 3.8 cases per million people and a median age of 69 years old.^4,7  A diagnosis of WM is confirmed with a bone marrow biopsy remarkable for infiltration of lymphoplasmacytic cells and the presence of monoclonal IgM paraprotein of any concentration.^2,8 Males are affected at a rate twice as high as females and incidence of white patients is more than twofold compared to black patients.⁷ Although the etiology of WM remains poorly understood, it is thought that the precursor condition known as monoclonal gammopathy of undetermined significance (MGUS), a premalignant plasma cell disorder, is the strongest risk factor for developing WM.⁹ Additionally, the risk of developing WM is increased amongst those with a personal history of autoimmune and infectious diseases such as Sjögren syndrome, autoimmune hemolytic anemia, polymyalgia rheumatica, pneumonia, septicemia, pyelonephritis, sinusitis, herpes zoster, and influenza.^9,10 Familial predisposition is common in WM and other B-cell malignancies.^11,12 In a series of 924 patients with WM, 27.5% of patients had a first-degree or second-degree relatives with a B-cell lymphoproliferative disorder.¹² Somatic mutations in the myeloid differentiation pathway response 88 (MYD88) gene (MYD88 L265P) are often present in patients with WM and at similar rates in those with or without retinopathy signs.³

Due to its large molecular pentamer structure and ability to form aggregates, 70%-90% of IgM produced is contained within the intravascular compartment, resulting in blood hyperviscosity and potentially a hyperviscosity syndrome in WM patients.^13,14 Hyperviscosity syndrome encompasses the triad of spontaneous bleeding from mucous membranes, visual changes, and neurological deficits ranging from a headache, dizziness, and hearing loss to seizures, ataxia, and coma.^2,15 When the history and physical exam findings are suspicious for hyperviscosity syndrome, a clinician should consider this as a medical emergency as end-organ damage can be discovered at the initial presentation of symptoms.¹⁶ Unfortunately, the course of WM remains indolent and uncurable, with a median survival of 10-11 years, and as a result, not all patients receive treatment.¹⁷ Treatment is introduced when constitutional symptoms arise with the goal of therapy to provide symptomatic relief and reduce the risk of end-organ damage.⁸

According to a review of 217 patients with WM, the most common presenting manifestations of this blood dyscrasia included anemia in 38% of cases, followed by funduscopic signs of retinopathy and hyperviscosity-related symptoms in 34% and 31% of cases, respectively.⁴       Additionally, approximately one-fourth of patients are asymptomatic at presentation.⁴ A more recent retrospective review of 50 patients with WM by Chen et al.³ in 2023, found retinopathy present in 56% of cases at the time of diagnosis, yet only 8% reported visual complaints or disturbances.¹⁸ Serum IgM values greater than 5,100 mg/dL have been demonstrated to be a risk factor for the presence of retinopathy in WM and fundus examinations are highly recommended in these situations.³

Retinal vascular tortuosity and dilation are the most commonly noted ocular signs of hyperviscosity-related retinopathy in WM patients, thought to be secondary to the high intravascular viscosity from IgM overproduction.^3,5 As serum hyperviscosity rises, venous stasis and blood flow turbulence results in increased intravascular pressure within the retinal circulation, leading to intraretinal hemorrhages, ischemic changes, and optic nerve edema.^3,5 SMD accompanying hyperviscosity-related retinopathy in WM is rare; yet, when present, it is likely to have a profound reduction in vision and a guarded visual prognosis.^3,6,19-22 Interestingly, SMD in WM patients do not show dye leakage on fluorescein or indocyanine green angiography, which is frequently seen in other conditions resulting in SMD, most notably, central serous retinopathy and exudative age-related macular degeneration.²³ Due to this lack of leakage on angiography, the source of the subretinal and intraretinal fluid in WM patients is not well understood. Two proposed pathological mechanisms include a disruption of retinal pigment epithelium pump function and increased osmotic pressure due to the hyperglobulinemia within the retina and/or discontinuity of the outer retinal layer which may allow IgM to infiltrate the subretinal space resulting in the serous detachment formation.^6,20,24 Immunofluorescent labeling has revealed the presence of IgM paraprotein within cystoid spaces of the outer plexiform layer in one patient and within the subretinal fluid of another patient.^24,25 In a case series by Baker et al.,⁶ 3 of 4 eyes demonstrated these focal outer retinal defects overlying subretinal fluid. In this present case, an outer retinal defect was appreciated in the right eye and no defect or disruption to the outer retinal layer was detected in the left eye.

While no standard treatment of hyperviscosity-related retinopathy in WM is currently recognized, the use of plasma exchange, or plasmapheresis and chemotherapy are commonly employed.^5,6 Menke et al.⁵ reported a case series of nine patients with hyperviscosity syndrome due to WM who underwent plasmapheresis treatment resulting in nearly 50% reduction in serum IgM and serum viscosity, and a subsequent improvement in retinopathy in all patients. Additionally, after treatment, the retinal venous diameter decreased by an average of 15.3% with a significant correlation between the percentage decrease in serum viscosity levels and percentage decrease in retinal venous diameter.⁵ Similarly, OCT-Angiography revealed a decrease in retinal capillary and large vessel density of one patient with hyperviscosity-related retinopathy and WM following plasmapheresis.²⁶

The use of intravitreal anti-VEGF in addition to systemic therapy alone to treat SMD associated with WM has yielded mixed results.^19,21,22 Kapoor et al.¹⁹ reported a case of accelerated resolution of SMD and marked visual improvement with intravitreal bevacizumab therapy. In comparison, Ratanam et al.²² documented a case using intravitreal bevacizumab monthly for 3 months which resulted in an improvement of visual acuity from 20/200 to 20/80 and reduction of central macular thickness; however, the SMD was still present. Additionally, another case report found only mild improvement in the SMD after a single intravitreal ranibizumab injection, but the presence of intraretinal fluid did completely resolve after 1 month.²¹

Since 2015, the use of BTK inhibitors has been increasing as a targeted therapy approach in combination with chemotherapy and immunotherapy medications as management of WM.²⁷ Ibrutinib, a first-generation BTK inhibitor, resulted in improvement of outcomes and quality of life in patients with WM and other B-cell malignancies, but adverse events, notably atrial fibrillation and ventricular dysrhythmias, caused discontinuation in up to 23% of patients in clinical studies.^27,28 One case report of a patient with WM documented near resolution of intraretinal hemorrhages and complete resolution of SMD over a 13-month period with ibrutinib treatment alone.²⁰ A phase III study compared zanubrutinib, a next-generation BTK inhibitor, to ibrutinib and found zanubrutinib was associated with fewer adverse events leading to dose reductions, treatment discontinuations and deaths, versus ibrutinib.²⁹ Recently, the first description of zanubrutinib treatment in a patient with WM and SMD was reported by Plante et al.³⁰ They noted persistent and minimally improved subretinal and intraretinal fluid after 5 months of zanubrutinib treatment. Interestingly, our case demonstrates a similar treatment duration of zanubrutinib with a comparable mild decrease of area and height of the SMD. Additional time may result in a more meaningful improvement of the SMD, but the long-term visual prognosis of this patient is guarded. Further research into the pathophysiology and management of SMD associated with WM is needed to identify an effective treatment.

CONCLUSION

A clinical presentation of hyperviscosity-related retinopathy with SMD warrants a prompt hematology evaluation for WM. Systemic treatment for WM, commonly consisting of plasma exchange or plasmapheresis and chemotherapy, may improve the signs of retinopathy and SMD. Use of intravitreal anti-VEGF to treat SMD have shown varied results in other reported cases. This case demonstrates a significant improvement in hyperviscosity-related retinopathy but persistent SMD resulting in minimal recovery of visual acuity following systemic treatment with zanubrutinib, a next-generation BTK inhibitor. Clinicians should be prepared to provide a guarded visual prognosis when significant SMD is noted at presentation and/or when a delay between diagnosis and initiation of treatment occurs.

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Andrew J. Crist, OD, FAAO

VA Central Ohio Healthcare System | Columbus, OH

Dr. Crist graduated from The Ohio State University College of Optometry and completed an ocular disease residency at VA Central Ohio and Chillicothe VA Medical Center. He practices at VA Central Ohio – Chalmers P. Wylie Chalmers P. Wylie Veterans Outpatient Clinic in Columbus, OH. He is also a Clinical Assistant Professor for The Ohio State University College of Optometry and is certified by the American Board of Certification in Medical Optometry.

Ravneet K. Meeta, OD

Center For Sight | Newark, OH

Dr. Meeta graduated from Pennsylvania College of Optometry and completed an ocular disease residency at VA Central Ohio and Chillicothe VA Medical Center. She currently practices at Center For Sight in Newark, OH.