Introduction

Waldenstrom’s macroglobulinemia (WM), as defined by the World Health Organization, is defined as a lymphoplasmacytic lymphoma with bone marrow involvement and IgM monoclonal gammopathy of any concentration [1]. It is characterized by anemia and lymphoplasmacytic infiltration of the bone marrow and often lymph nodes, spleen, and rarely other extranodal sites. Infiltration in the central nervous system (CNS) is very rare and referred to as Bing–Neel (BN) syndrome. To date, only case reports and several very small patient series have been published. We present a case of BN syndrome including diagnosis, evaluation, and treatment. We searched Medline using the search terms “Waldenstrom’s macroglobulinemia and central nervous system” and “Bing–Neel” and reviewed the literature for all cases of CNS involvement to analyze the characteristics of this complication, treatments used and outcomes thus creating the largest pooled series of 32 patients.

Case report

A 62-year-old right-handed woman with a history of WM presented in 2006 with headache, sudden onset aphasia, and a right lower facial droop of 30 min duration. In the week prior, she had malaise, nausea, and headache which all resolved.

She was diagnosed with WM in 1994 with IgM macroglobulinemia and hypercellular bone marrow consisting of small lymphocytes and plasmacytoid lymphocytes. She was monitored for 4 years but then developed worsening anemia and more prominent bone marrow involvement. She was treated with 2-chlorodeoxyadenosine (2-CdA, cladribine) in 1998 with partial remission. After relapsing, she was treated with rituximab in 2000 and again in 2003, but she developed pleurisy with effusion, so rituximab was stopped and 2-CdA was restarted with some response. In 2004 she was treated with bortezomib; during this time, she developed transient word finding difficulty (November 2004) and was diagnosed with a transient ischemic attack related to a newly discovered patent foramen ovale (PFO). Anticoagulation with warfarin was started; bortezomib was discontinued. WM relapsed in 2005 and she was treated with rituximab, cyclophosphamide, vincristine, and dexamethasone for six cycles followed by maintenance rituximab every 3 months. Another transient episode of aphasia occurred 2 months prior to admission and she was continued on warfarin. She also had recurrent pleural effusions, requiring bilateral chest tube thoracostomy placement for drainage and pleurodesis; the etiology of the effusions was unknown but no malignant cells were seen. She also developed paroxysmal supraventricular tachycardia which was treated with metoprolol.

On presentation in 2006 her examination was unremarkable except for aphasia with poor comprehension and fluency, dysnomia, and a mild right lower facial weakness. Laboratory examination revealed an erythrocyte sedimentation rate of 50 mm/h, INR 3.4, and serum viscosity 1.5 centipoise (normal 1.4–1.8 centipoise). Serum protein electrophoresis and immunofixation revealed a restricted gamma band and monoclonal IgM kappa light chains. Quantitative serum IgM was 393 mg/dl. Cryoglobulin testing was negative.

Electroencephalogram showed mild diffuse cerebral dysfunction and moderate left frontotemporal slowing but no epileptiform discharges. Computed tomography (CT) of the head showed patchy and confluent hypoattenuation in the periventricular and deep subcortical white matter, with some focal predominance involving the anterior limb of the left internal capsule. Magnetic resonance imaging (MRI) of the brain is shown in Fig. 1. There was no diffusion restriction. MR angiogram and venogram were unremarkable. The PFO previously diagnosed was not seen on the current echocardiogram.

Fig. 1
figure 1

MRI findings. a Axial FLAIR sequence demonstrates abnormal T2-hyperintensity extending from the periventricular to subcortical white matter. The linear and oval configuration of several of the lesions is consistent with a perivascular distribution. b Axial T1 image with gadolinium demonstrates linear enhancement corresponding to the T2-hyperintensities. c Coronal T1 image with gadolinium demonstrates enhancement with confluent regions

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Cerebrospinal fluid (CSF) examination revealed an opening pressure of 270 mm H2O, 11 white blood cells/mm3, glucose 47 mg/dl (serum glucose 97 mg/dl), and protein 136 mg/dl. IgG index was 0.42. Protein electrophoresis immunofixation of the CSF showed the presence of monoclonal IgM kappa gammopathy. CSF cytology and flow cytometry was negative for malignancy on two occasions; there was T cell predominance in the cells seen. CSF viral studies were negative.

Stereotactic biopsy was performed targeting a small-enhancing lesional component in right corona radiata-internal capsular region (anterior limb). Histopathology is described in Fig. 2 and was consistent with BN syndrome. Conspicuous kappa immunoglobulin light-chain restriction was evident by concurrent flow-cytometric immunophenotyping (cell-surface; Fig. 3).

Fig. 2
figure 2

Histologic findings. a Histomicrograph, stereotactic biopsy right frontal deep-white matter lesion: The enlarged illustration (left) depicts enlarged area of perivascular infiltrate by small lymphocytes with mostly round nuclei and clumped chromatin. The inset shows multiple dense perivascular infiltrates with a loose scattering of single cells in surrounding areas. Immunohistochemistry confirms their B-cell nature (CD20+). b The larger picture shows that the infiltrating cells are smaller than endothelial cells, are mature appearing lymphocytes with an admixture of plasmacytoid lymphocytes and rare plasma cells

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Fig. 3
figure 3

Flow cytometric findings. (a, left) Flow-cytometric analysis detects the presence of CD45+ lymphocytes, which comprise CD19+ B-cells. (b, upper right, and c, lower right) Specific gating on this CD19 population (arrows) indicates a population of CD10-B-cells with conspicuous kappa light-chain restriction. These data are consistent with a monoclonal B-cell population, based on restriction for cell-surface immunoglobulin light chain

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The episodic aphasia and facial droop was felt to be focal seizures rather than transient ischemic events, the patient was started on levetiracetam 500 mg twice daily and warfarin was discontinued. The patient was treated with four monthly cycles of methotrexate 3.5 mg/m2 (day 1), vincristine 1.4 mg/m2 (day 1), and procarbazine 100 mg/m2 daily for 7 days with no improvement in MRI brain. The patient developed painful palpable mass in her right humerus; bone marrow replacement was found on MRI, which was consistent with WM or plasmacytoma and treated with 30 Gy of radiation therapy resulting in decreased size of lesion and resolved pain. Rituximab 750 mg/m2 was started twice weekly for five cycles. Brain MRI after the rituximab showed a minor improvement in enhanced and FLAIR sequences. Two courses of fludarabine 20 mg/m2 day 1–4 once a month were added to rituximab without further improvement on MRI, so it was discontinued due to myelotoxicity and lack of additive response. At this time the patient was re-staged. Fluorodeoxyglucose positron emission tomography (FDG-PET) of the brain did not show any areas of uptake. FDG-PET of the body showed nonspecific uptake in the left anterior neck, over the apex of the right lung, posteromedial chest wall, right paraspinal muscles, right anterior abdominal wall, and left iliac and femur. Bone marrow biopsies of the iliac crests in April and October 2007 showed hypocellularity with no morphologic evidence of disease. The samples were insufficient for B-cell studies by flow cytometry to assess clonality. MRI of her left thigh showed bone marrow replacement and necrosis in the proximal two-thirds of the femur. Since the findings on follow-up right arm, left leg, and brain MRI were stable and the serum IgM remained low, rituximab was tapered to a monthly schedule and then every 6 weeks, on which she continues currently. There has been no recurrence of neurological symptoms or progression of her systemic and CNS disease based on neurological examination and brain MRI.

Discussion

In 1944, discovery of macroglobulinemia associated with constitutional symptoms, anemia, thrombocytopenia, and lymphocytic and lymphoplasmacytic infiltration of bone marrow was reported by Waldenstrom [2]. Eight years prior, Bing and Neel described a syndrome of anemia with neurological dysfunction associated with increased blood and CSF globulins [3]. The neurological patterns they encountered included paralysis, headache, and vomiting, and they were associated with perivascular lymphoplasmacytoid infiltrates in the CNS, bone marrow, lymph nodes, spleen, and liver on pathology. Bing–Neel syndrome is currently defined as WM with CNS involvement of perivascular infiltration of small lymphocytes, lymphoplasmacytoid cells, and plasma cells [4]. The areas of infiltrate can be small and numerous and can coalesce to be more solid and tumorous [5]. We reviewed all published cases reviewing presentation, laboratory, pathology and imaging findings as well as treatments and outcomes since no large series exist. Thirty-two cases of BN syndrome have been published and are summarized in Table 1 with a summary of most common findings in Table 2.

Table 1 Cases reported on Bing–Neel syndrome
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Table 2 Findings in Bing–Neel syndrome [1, 3–16, 19, 25–36]
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CNS manifestations of WM include strokes, other focal or multifocal brain syndromes, diffuse encephalopathies, subarachnoid hemorrhage, or a combination of these; BN syndrome refers specifically to the involvement of perivascular infiltrates rather than stroke or hemorrhage due to hyperviscosity [6]. Symptoms commonly include seizures, confusion, cognitive decline, headache, blurry or cloudy vision, psychiatric manifestations, pain, numbness, paresthesias, hearing loss, and weakness [7]. Such manifestations result directly from the locus of the involvement by infiltration or indirectly by hyperviscosity.

Serum laboratory tests associated with BN syndrome only reflect WM. At least 5% macroglobulinemia, serum protein electrophoresis with a monoclonal IgM kappa or lambda light chain restriction, and bone marrow lymphoplasmacytic infiltrate are necessary to diagnose WM. The erythrocyte sedimentation rate may be >100 mm/s and there is often a normocytic, normochromic anemia. Variable findings include elevated serum viscosity, elevated transaminases, cryoglobulins, and rarely Bence Jones proteinuria [7–9]. It is interesting that in our patient, other than the right humeral and asymptomatic left femoral involvement noted on imaging, her disease was stable and IgM remained <425 mg/dl.

Computed tomography of the brain may reveal a hypodensity due to mass effect or infarction, or hyperdensity from subarachnoid hemorrhage [5, 6, 10]. MRI often illustrates T2 and FLAIR hyperintensities with edema, which is isointense on T1 and may enhance, in the area or areas of involvement but can be normal [5, 8, 11–15]. FDG-PET demonstrates areas of hypometabolism that correspond to areas of involvement on MRI [12, 15]. Electroencephalography may show generalized slowing, indicative of cerebral dysfunction, or focal epileptiform activity [4, 8, 16].

Cerebrospinal fluid findings include an elevated opening pressure, lymphocytosis with WBC between 100 and 500 cells/mm3, total protein >100 mg/dl, and normal or decreased glucose [7–9]. IgM kappa or lambda band restriction can be seen with immunofixation; more commonly in diffuse rather than in coalescent CNS disease. Cytology and flow cytometry may reveal small lymphoplasmacytoid cells that are CD20 positive, as well as CD19, CD22, CD38, and/or CD45 positive, CD5 positive or negative, and CD10 negative [8, 11, 14]. While a positive test substantiates the diagnosis, negative results do not exclude it as in our case, given the low sensitivity of cytological testing due to the paucity or absence of neoplastic cells.

Biopsy is often required for definitive diagnosis. Multiple reports have demonstrated the same pathology in the CNS as in the bone marrow, spleen, lymph nodes, and liver. Bone marrow analysis shows nodular, diffuse, and/or interstitial infiltrates of small lymphocytes, plasmacytoid lymphocytes, and plasma cells with or without paratrabecular aggregates are seen [1]. On autopsy, gross examination of brain tissue reveals softened, circumscribed, and grayish-yellow or grayish-red areas [4, 6, 16]. Microscopically, there is a lymphoplasmacytic infiltrate surrounding the Virchow-Robin spaces. Mature plasma cells penetrate into the parenchyma and produce IgM kappa or lambda light chains. Intranuclear periodic acid-Schiff (PAS) positive material can be seen. As stated above, these cells have variable cell marker expression. Once present, the plasma cells cause reactive changes, such as proliferation of reticulum cells within Virchow Robin spaces, as well as foamy histiocytes, astrocytes, and microglia. Demyelination with axonal loss may occur in irregular patches. Mural PAS positive fluid may be found in the blood vessel walls and permeating the surrounding white matter [4–6, 11, 15, 16]. Electron microscopy demonstrates cytoplasmic inclusions in pericytes and macrophages and membrane bound inclusions consisting of microtubules in gently curved arrays singly or in small groups [16].

Weiss et al. [17] and Frantzen et al. [18] proposed that the CSF concentration of paraprotein has no correlation with neurological dysfunction since several patients had CSF monoclonal paraprotein without neurological disease. Hansotia et al. [19] confirmed these findings but speculated that when the CSF paraprotein concentration increases out of proportion to the albumin, there is usually neoplastic lymphoplasmacytoid cell proliferation beyond the blood brain barrier.

The prognosis of Bing–Neel syndrome had historically been poor. Various chemotherapeutic agents have been used though no clinical trials have been performed due to the rarity of the syndrome (Table 1). Remission has been reported with the use of intrathecal methotrexate alone, and improvement has been noted with carmustine intrathecally and intravenously, or with radiation therapy (20–40 Gy of whole brain radiation therapy) [5, 8, 9]. 2-Chlorodeoxyadenosine, a purine analog, has been reported to have an 85% efficacy alone in previously untreated WM without CNS involvement (N = 26) [20]. When 2-chlorodeoxyadenosine was combined with cyclophosphamide and prednisone and given in 6 courses to 19 patients with lymphoproliferative disorders (3 patients had WM), the overall response rate was 88%, but none of those patients had CNS disease [21]. Richards successfully used 2-chlorodeoxyadenosine to treat a patient with leptomeningeal involvement of WM, and he suggested its success may be due to increased blood brain barrier penetration in meningeal disease and slower clearance from the CSF [22]. Rituximab has also been used with good success in systemic WM and was moderately effective in our patient but not in a case reported by Welch et al. [15, 23–26].

Conclusion

We present a case of BN syndrome and compiled the largest series to date of 32 patients with this entity based on a comprehensive review of the published literature. Bing–Neel syndrome is a rare complication of WM that varies in neurologic presentation with focal, multifocal, or diffuse symptoms. Imaging and CSF are often abnormal, though the latter may not be. While prognosis has historically been poor, this complication appears more amenable to treatment with responses or disease stabilization using the latest chemotherapeutic agents with or without radiation therapy.