“All the soarings of my mind begin in my blood:” central nervous system complication of Waldenström macroglobulinemia

A 76-year-old man was admitted to our hospital for one month of progressive word finding problems. He was diagnosed with Waldenstr€ om macroglobulinemia (WM) two years prior when he presented with fatigue and anemia. The patient carried the MYD88 L265P gene mutation. In the past year, he had developed pancytopenia, elevated serum viscosity, enlarged intra-abdominal lymph nodes, and bilateral pleural effusions. Treatment with monthly infusions of bendamustine and rituximab had been initiated four months before presentation. His absolute lymphocyte count was 1.51 k/uL at the start of therapy, 0.92 k/uL at Cycle 2, 0.75 k/uL at Cycle 3, 1.64 k/uL at Cycle 4, and 1.88 k/uL at four week follow-up after Cycle 4. His counts reached a nadir of 0.24 k/uL midway through the treatment regimen. The patient’s word finding difficulties suggest a lesion in the central nervous system (CNS), specifically in the peri-sylvian region of the left hemisphere, which includes Broca’s area (the center for language expression) anteriorly, Wernicke’s area (the center for language comprehension) posteriorly, and subcortical white matter fibers (arcuate fasciculus) that connect these two regions. The history of WM, and current immunocompromised state due to the disease itself and chemotherapy, raise a broad differential for his neurological symptoms. The most concerning etiologies include arterial or venous occlusion and cerebral infarction due to serum hyperviscosity, cerebral or meningeal inflammation from WM (Bing-Neel syndrome [BNS]), paraneoplastic or other autoimmune encephalitis, or opportunistic infection. On examination, he was alert and interactive with mild bradyphrenia. He had impaired fluency with frequent phonemic and semantic paraphasic errors. He could follow simple commands and repeat short but not longer or more complex sentences. He had right-sided brachiofacial weakness. The remainder of his neurological exam was normal. Abnormal laboratory studies included hemoglobin 11.2 g/dL, white blood cells (WBC) 2.09 k/uL with absolute neutrophil count 0.38 k/uL, absolute lymphocyte count 0.54 k/uL and platelet count 142 3 10/L. Serum protein electrophoresis demonstrated a monoclonal spike in the gamma region of 0.34 g/dL and immunofixation confirmed a monoclonal IgM Kappa paraprotein. Serum IgM level was 379 mg/dL. The patient was in a partial response after 4 cycles of bendamustine and rituximab. The examination supports a mixed aphasia with elements of nonfluency and impaired comprehension that localizes to the left frontal and temporal lobes. The presence of pancytopenia and concurrent immunosuppressive therapy places this patient at elevated risk for progressive multifocal leukoencephalopathy (PML), toxoplasmosis, and primary CNS lymphoma. Furthermore, one should consider CNS abscesses or meningo-encephalitides from fungal (Aspergillus, Cryptococcus), viral (HSV, CMV, VZV) or mycobacterial species. BNS has been described in patients who are responding to therapy for systemic WM [1]. Therefore, the patient’s response to therapy does not exclude the diagnosis of BNS. With a serum IgM level less than 3,000 mg/dL, hyperviscosity is unlikely. The next step in clarifying the diagnosis is a brain MRI with gadolinium. MRI showed multifocal well-demarcated nearly confluent areas of abnormal T2 hyperintensity, predominantly in the subcortical white matter of the left frontal, temporal, parietal, and right frontal lobes (Fig. 1A,B). A dominant lesion in the left anterior frontal sub-cortical white matter was edematous and exerted mass effect on adjacent structures. There was modest reduced diffusivity at the periphery of the left frontal lesion (Fig. 1C). There was no abnormal enhancement of this lesion on post-contrast images. As part of staging for WM, the patient underwent a full body positron emission tomography (PET) scan that showed no systemic 18F-FDG-avid lesions. The left frontal lobe lesion showed reduced 18F-FDG uptake (Fig. 1D). The radiographic findings support a multifocal process with a tumefactive lesion in the left frontal lobe. The juxtacortical white matter hyperintensities on T2-weighted images are consistent with an infiltrative condition. The absence of prominent reduced diffusivity makes primary CNS lymphoma or abscess less likely. Furthermore, the absence of contrast enhancement and hypometabolism on PET scan are atypical for high-grade primary or metastatic brain neoplasms. The radiological differential includes PML or BNS. PML produces a pattern of demyelination that is predominantly localized to the frontal and parieto-occipital lobes. Lesions are generally hypointense and