Waldenström macroglobulinemia (WM) is a malignant lymphoproliferative disorder characterized by overproduction of monoclonal IgM. It is a type of non-Hodgkin lymphoma, also called lymphoplasmacytic lymphoma. The bone marrow and lymph nodes are infiltrated by pleomorphic B lymphocytes, leading to a massive increase in serum IgM.
In 1944, Swedish internist Jan Gösta Waldenström first reported two cases with symptoms due to increased serum viscosity. The triad consisted of mucosal bleeding, visual changes, and neurological abnormalities. The term “hyperviscosity syndrome” was coined by Fahey in 1965.
The incidence is rare, with 2 to 5 cases per million people per year 1). The median age at diagnosis is about 69 years, and the male-to-female ratio is approximately 2:1, showing male predominance 1). It is more common in Caucasians, and onset before age 50 is rare. It accounts for 1 to 2% of all hematologic malignancies.
Approximately 30 to 40% of WM patients develop retinopathy due to serum hyperviscosity. Ophthalmic findings may be the initial symptom of WM, and dilated fundus examination can sometimes be the starting point for diagnosis.
Approximately 30 to 40% of WM patients develop hyperviscosity-related retinopathy. In particular, when IgM protein levels reach 3 g/dL or higher, hyperviscosity syndrome is more likely to occur, and fundus changes tend to appear.
Ocular symptoms of hyperviscosity-related retinopathy are primarily caused by retinal circulatory disorders.
Fundus findings correlate with the degree of hyperviscosity. Since this disease is systemic, it always appears bilaterally.
Mild to Moderate
Peripheral venous dilation and tortuosity: Engorgement of retinal veins starting from the far periphery. Can be confirmed by indirect ophthalmoscopy with scleral depression.
Peripheral hemorrhage: Preceded by punctate and blot hemorrhages in the peripheral retina.
Sausage-like (beaded) changes: Segmental dilation of retinal veins. A characteristic finding in WM (macroglobulinemia).
Severe
Central hemorrhage / macular edema: Hemorrhage extends to the posterior pole and macula, causing vision loss.
Optic disc edema: Disc swelling appears with progressive hyperviscosity.
Serous macular detachment: Accumulation of subretinal fluid. If left untreated, it can lead to permanent vision loss.
Retinal vein occlusion (bilateral): Occurs when severe venous compression and engorgement progress.
The hemorrhages are diverse in nature, including microaneurysms, dot-blot, and flame-shaped hemorrhages. FA (fluorescein angiography) shows prolonged retinal circulation time, capillary nonperfusion, and microaneurysms. In a report documenting FA before and after plasma exchange in a WM case, occlusion of peripheral white-centered lesions and capillary dropout were observed1). OCT is useful for monitoring macular edema and hyperreflective material in the outer nuclear layer1).
When the macula is not affected, peripheral hemorrhage may not affect vision. However, progression of serous macular detachment or macular edema can lead to permanent vision loss. Since retinal findings improve over several months with systemic treatment for WM, regular ophthalmologic evaluation and comprehensive management in collaboration with an internist are important.
WM is primarily considered a sporadic disease, but genetic background has also been reported. Many patients have a deletion of 6q21-22.1, and first-degree relatives may also have B-cell diseases.
A history of IgM-MGUS (monoclonal gammopathy of undetermined significance) significantly increases the risk of developing WM in the future. Most WM cases develop following MGUS.
Other risk factors include association with hepatitis C and autoimmune diseases such as Sjögren’s syndrome.
Increased serum IgM is the main cause of hyperviscosity. When IgM levels reach 3 g/dL or higher, hyperviscosity syndrome frequently occurs, and fundus changes are likely to appear.
A definitive diagnosis of WM requires meeting the following two major criteria (Mayo Clinic criteria).
The main testing procedures are as follows:
Fundus findings may be the initial symptom of WM. If hyperviscosity syndrome is suspected, a thorough ophthalmic examination is recommended.
Ocular findings of hyperviscosity-related retinopathy may resemble those of other diseases.
Yes. Characteristic findings on dilated fundus examination (bilateral retinal vein sausage-like dilation, retinal hemorrhages) may be a clue to the initial diagnosis. If an ophthalmologist suspects hyperviscosity syndrome, it is important to refer to hematology and prompt serum protein electrophoresis and viscosity measurement.
Treatment of WM is performed in two stages: management of acute hyperviscosity syndrome and systemic treatment to suppress IgM production. Ophthalmic treatment is performed as needed in parallel with systemic treatment.
It is the first choice for acute symptoms caused by hyperviscosity (retinopathy, neurological symptoms, bleeding tendency). Since more than 80% of IgM is present in the intravascular space, plasmapheresis is effective.
Chemotherapy is administered to control serum IgM and prevent its re-elevation.
Systemic treatment of the underlying disease is prioritized, but ophthalmic intervention according to retinal findings is also performed. Close collaboration with an internist to report ophthalmic conditions is important.
Plasma exchange only temporarily lowers IgM. To prevent IgM from rising again, subsequent chemotherapy to treat WM itself is necessary. Combining plasma exchange with chemotherapy can lead to long-term improvement in retinal findings 1).
The central pathology of WM is bone marrow infiltration by clonal lymphoplasmacytic cells and overproduction of pentameric IgM.
IgM significantly increases blood viscosity due to the following properties.
Normal serum viscosity is 1.4–1.8 times that of water (cP) at body temperature. According to multiple studies, hyperviscosity symptoms are unlikely below 4 cP, but symptoms tend to occur above 5.0 cP.
Viscosity is highest in venules. The viscous fluid breaks through the venule walls, causing microvascular hemorrhage. This is observed as central retinal hemorrhage and vascular dilation in the retina.
Autoregulatory venous dilation occurs, followed by venous stasis and increased intravascular pressure, leading to hypoxia of the retinal vascular endothelium. This results in vascular tortuosity, retinal hemorrhage, exudation, and retinal vein occlusion1).
Bone marrow biopsy may reveal Dutcher bodies (cytoplasmic inclusions positive for periodic acid–Schiff stain). Excessive proliferation of mast cells is also characteristic, and they overexpress CD40 ligand, promoting B-cell proliferation.
OCT-A (OCT angiography) is a new method that can noninvasively evaluate retinal perfusion deficits. It can quantitatively capture retinal vascular changes that were previously only qualitatively assessed by conventional fluorescein angiography.
Schatz et al. (2021) applied an image analysis algorithm to OCT-A images before and after plasma exchange in a case of WM-related hyperviscosity retinopathy, and objectively demonstrated that capillary density decreased from 47.62% to 45.35% and large vessel density from 18.87% to 10.16% 1). This is one of the few reports that quantitatively evaluated the treatment effect of hyperviscosity retinopathy using OCT-A.
The decrease in vessel density after treatment may be due to (1) permanent destruction of capillaries caused by hypoxia and pseudo-occlusion events due to hyperviscosity, or (2) artifacts reflecting a reduction in vessel diameter 1). Combining OCT-A with image analysis algorithms is expected to guide treatment duration and monitor recurrence.
Previous reports have described multimodal imaging findings using intravitreal bevacizumab injection for WM-related immunogammopathy maculopathy, showing reduction of serous retinal detachment and residual outer retinal atrophy 1). Its role as a standard treatment has not been established.
