How we manage Bing-Neel syndrome.

Bing-Neel syndrome (BNS) is an uncommon presentation of Waldenström macroglobulinaemia (WM), seen during the course of the disease in about 1% of patients. BNS occurs when WM cells gain access to the central nervous system (CNS) causing neurological deficits. The diagnosis of BNS is suggested by the presence of radiological abnormalities, such as leptomeningeal enhancement on magnetic resonance imaging and confirmed by the presence of clonal lymphoplasmacytic cells and MYD88 L265P in the cerebrospinal fluid. The treatment of BNS requires agents with good penetration into the CNS, such as fludarabine, methotrexate and cytarabine. The novel Bruton Tyrosine Kinase inhibitor ibrutinib has shown CNS-penetrating properties, and recent data suggest a therapeutic role in BNS. In this review, we will discuss the clinical and pathological features, diagnostic criteria, treatment options and outcomes of patients with BNS.

The use of droplet digital PCR in liquid biopsies: A highly sensitive technique for MYD88 p.(L265P) detection in cerebrospinal fluid.

The gold standard for diagnosis of central nervous system lymphomas still regards a stereotactic brain biopsy, with the risk of major complications for the patient. As tumor cells can be detected in cerebrospinal fluid (CSF), CSF analysis can be used as an alternative. In this respect, mutation analysis in CSF can be of added value to other diagnostic parameters such a cytomorphology and clonality analysis. A well-known example of targeted mutation analysis entails MYD88 p.(L265P) detection, which is present in the majority of Bing Neel syndrome and primary central nervous system lymphoma (PCNSL) patients. Unfortunately, tumor yield in CSF can be very low. Therefore, use of the highly sensitive droplet digital PCR (ddPCR) might be a suitable analysis strategy for targeted mutation detection. We analyzed 26 formalin fixed paraffin embedded (FFPE) samples (8 positive and 18 negative for MYD88 p.(L265P) mutation) by ddPCR, of which the results were compared with next generation sequencing (NGS). Subsequently, 32 CSF samples were analyzed by ddPCR. ddPCR and NGS results on FFPE material showed 100% concordance. Among the 32 CSF samples, 9 belonged to patients with lymphoplasmacytic lymphoma (LPL) and clinical suspicion of Bing Neel syndrome, and 3 belonged to patients with PCNSL. Nine of these samples tested positive for MYD88 p.(L265P) (8 LPL and 1 PCNSL). This study shows that sensitive MYD88 mutation analysis by ddPCR in CSF is highly reliable and can be applied even when DNA input is low. Therefore, ddPCR is of added value to current diagnostic parameters, especially when the available amount of DNA is limited.

Bing-Neel syndrome, a rare complication of Waldenström macroglobulinemia: analysis of 44 cases and review of the literature. A study on behalf of the French Innovative Leukemia Organization (FILO).

Central nervous system involvement by malignant cells is a rare complication of Waldenström macroglobulinemia, and this clinicopathological entity is referred to as the Bing-Neel syndrome. There is currently no consensus on the diagnostic criteria, therapeutic approaches and response evaluation for this syndrome. In this series, we retrospectively analyzed 44 French patients with Bing-Neel syndrome. Bing-Neel syndrome was the first manifestation of Waldenström macroglobulinemia in 36% of patients. When Waldenström macroglobulinemia was diagnosed prior to Bing-Neel syndrome, the median time interval between this diagnosis and the onset of Bing-Neel syndrome was 8.9 years. This study highlights the possibility of the occurrence of Bing-Neel syndrome without any other evidence of progression of Waldenström macroglobulinemia. The clinical presentation was heterogeneous without any specific signs or symptoms. Biologically, the median lymphocyte count in the cerebrospinal fluid was 31/mm(3). Magnetic resonance imaging revealed abnormalities in 78% of the cases. The overall response rate after first-line treatment was 70%, and the overall survival rate after the diagnosis of Bing-Neel syndrome was 71% at 5 years. Altogether, these results suggest that Bing-Neel syndrome should be considered in the context of any unexplained neurological symptoms associated with Waldenström macroglobulinemia. The diagnostic approach should be based on cerebrospinal fluid analysis and magnetic resonance imaging of the brain and spinal axis. It still remains difficult to establish treatment recommendations or prognostic factors in the absence of large-scale, prospective, observational studies.

One-step molecular detection of the MYD88 L265P mutation by unlabeled probe genotyping analysis.

The aim of our study was to establish an unlabeled probe genotyping approach for rapid detection of the MYD88 L265P mutation in the differential diagnosis of WaldenstrÓ§m macroglobulinemia patients. Analytical and clinical validation of the assay was performed using serially diluted amplicon-cloned standards, 14 clinical bone marrow aspirate samples, and 30 peripheral blood samples from healthy donors, respectively. The analytical validation results showed that the assay is able to reproducibly identify as low as 10% of the L265P mutant. Clinical validation results showed improved detection sensitivity for the L265P mutation compared to Sanger sequencing. With the simplicity, cost-effectiveness, specificity and rapidity, we foresee that the unlabeled probe HRM assay is a good alternative to substitute current established methods for routine diagnostic testing of the MYD88 L265P mutation.

MYD88 L265P mutation contributes to the diagnosis of Bing Neel syndrome.

Bing-Neel syndrome (BNS), a rare neurological syndrome associated with Waldenström macroglobulinaemia (WM), is a direct involvement of the central nervous system by lymphoplasmacytoid cells characterized with an adverse prognostic. The MYD88 L265P mutation has been identified in the vast majority of patients with WM. The diagnosis of BNS is often challenging because of the variety of clinical presentations associated with difficult histological techniques. We hypothesized that identification of MYD88 L265P mutation in the cerebrospinal fluid (CSF) would contribute to the diagnosis of BNS in addition to imaging, flow cytometry and cytology. We identified MYD88 L265P mutation in the CSF and the bone marrow of all cases of BNS using quantitative polymerase chain reaction qPCR and Sanger sequencing. Copy neutral loss of heterozygosity including MYD88 was observed in one case. No mutation of CXCR4, CD79A and CD79B was observed in parallel. We further showed that monitoring the quantitative expression of MYD88 L265P mutation might be a useful molecular tool to monitor response to chemotherapy using qPCR. In conclusion, identification of MYD88 L265P mutation might be a new molecular-based biomarker tool to add to the diagnostic and monitoring armamentarium for BNS.

Novel diagnostic approaches in Bing-Neel syndrome.

The central nervous system (CNS) manifestations of Waldenström's macroglobulinemia (WM) are known as the Bing-Neel syndrome (BNS). Patients with BNS can be classified into Group A and Group B based on the presence of lymphoplasmacytoid (LMP) cells within the brain parenchyma, leptomeninges, dura, and/or cerebrospinal fluid (CSF). To identify characteristic imaging findings for both Group A and Group B patients, we reviewed all 36 cases (26 referenced, 10 unreported) of proven WM with CNS symptoms, CSF analysis and/or biopsy, and magnetic resonance imaging (MRI) of the brain and/or spinal cord. Enhancement on MRI suggests invasion of the central neuraxis by LMP cells, and can help distinguish between Group A and Group B patients. In addition to differentiating true WM lesions in the CNS from ischemia, hyperviscosity events, and demyelinating lesions, evaluation of brain and spinal cord with gadolinium-enhanced MRI has the potential to guide management.

Bing-Neel syndrome: a case report and systematic review of clinical manifestations, diagnosis, and treatment options.

BACKGROUND: Bing-Neel syndrome is an extremely rare neurologic complication of Waldenström macroglobulinemia (WM) that was first described in 1936. It is associated with central nervous system infiltration by neoplastic lymphoplasmacytoid and plasma cells with or without cerebrospinal fluid (CSF) hyperglobulinemia. CASE REPORT: We report a case of a 69-year-old white man with a 10-year history of WM. He was diagnosed with Bing-Neel syndrome based on magnetic resonance imaging and pathology studies of CSF. In addition, a comprehensive review of the reported cases of Bing-Neel syndrome in the up-to-date English-language literature was performed. RESULTS: Our patient underwent successful treatment with cranial radiation and intrathecal chemotherapy. He has been in clinical and pathologic remission for 3 years following the completion of his treatment. Based on our literature review, we also summarize and discuss clinical manifestations, diagnosis, and treatment options for Bing-Neel syndrome. CONCLUSION: Bing-Neel syndrome is a rare and potentially treatable complication of WM. Patients with a history of WM presenting with neurologic symptoms should be evaluated for possible Bing-Neel syndrome. Cranial radiation therapy alone or in combination with intrathecal chemotherapy is more likely to achieve sustainable remission than intrathecal chemotherapy alone.

Bing-Neel Syndrome revisited.

Since the 1936 seminal description of neurologic difficulties in patients with hyperglobulinemia, the "Bing-Neel Syndrome" has been applied to a range of neurologic symptoms. To clarify the central nervous system (CNS) manifestations of Waldenström macroglobulinemia (WM), we performed a literature search (years 1936 to 2008) of reports of "Bing-Neel Syndrome" or "WM affecting the CNS" (WM-CNS). We excluded cases of hyperviscosity, malignant transformation, vasculitis, and purely ophthalmologic manifestations. After analysis of symptoms, cerebrospinal fluid (CSF), imaging, and histopathology, we separate WM-CNS into (1) lymphoplasmacytoid cells infiltrating the CNS, and (2) a non-cellular form, in which other mechanisms, such as IgM deposition, might produce the neurologic symptoms.

'Indolent' Waldenstrom's macroglobulinemia and a cerebrospinal fluid protein level of 16 g/L.

Waldenstrom's macroglobulinemia occasionally presents with neurological manifestations. Very rarely, it is due to a central nervous system localization, the so-called Bing Neel Syndrome. We report a patient with an 'indolent' systemic disease and surprisingly a concomitant major CNS involvement.

[Leptomeningeal tumor cell infiltrations as a first manifestation of an immunocytoma (Waldenstrom's macroglobulinemia)]. / Leptomeningeale Tumorzellinfiltration als Erstmanifestation eines Immunozytoms (M. Waldenström).

Immunocytoma (Waldenstrom's macroglobulinemia) is a rare chronic lymphoproliferative disorder of B-cell origin. It is characterized by the presence of large amounts of circulating monoclonal immunoglobulin M (IgM) and lymphoplasmocytoid bone marrow infiltration. Affection of the peripheral nervous system is common and causes polyneuropathy (5-10%). An isolated leptomeningeal infiltration by neoplastic cells is very rare and has been reported in few cases only. The diagnosis is difficult, in particular if cerebrospinal fluid (CSF) cytology is inconclusive. We present the case of a patient who developed a personality disorder and cognitive impairment. Initial CSF findings were compatible with chronic lymphocytic (aseptic) meningitis. The serologic detection of IgM paraproteinemia and bone marrow cytology suggested immunocytoma. The selective analysis of B-cell clonality in both whole CSF cell lysates and individual CSF cells using polymerase chain reaction (PCR) based amplification of the rearranged CDR3 region of the IgH gene revealed the presence of a monoclonal B-cell population and was diagnostic for leptomeningeal tumor cell infiltration by immunocytoma.

Impairment of electrophysiological function of astrocytes by cerebrospinal fluid from a patient with Waldenström's macroglobulinemia.

Patients with the Bing Neel type of Waldenström's macroglobulinemia often present with global neurological symptoms. In this case report, we investigated the effects of cerebrospinal fluid (CSF) of a such a patients (CSF-WM), who presented with seizures and psychomotor slowing, on the electrophysiological properties of cultured rat neurons and astrocytes. Membrane potential and Na+ and K+ currents of neurons were unaffected. Astrocytes, however, were significantly depolarized from -77.6 +/- 8.2 mV to -48.0 +/- 7.6 mV (38%) by CSF-WM. The depolarization was markedly reduced after CSF-WM heat inactivation or after pre-incubation of astrocytes with dexamethasone (1 microM). Astrocytes are electrophysiologically active cells, which control local ionic micro-environment. Therefore, we conclude that global neurological symptoms in the Bing Neel type of Waldenström's macroglobulinemia like generalized seizures can result from an impairment of glial cells electrophysiological functions.

[Involvement of central nervous system disclosing Waldenstrom's disease: demonstration of intrathecal secretion of immunoglobulin M]. / Atteinte des fonctions supérieures révélant une maladie de Waldenström: mise en évidence d'une secrétion intrathécale d'immunoglobuline M.

We report the case of a 68-year old woman complaining of disorders of memory and persistent headaches in whom the diagnosis of Waldenström's macroglobulinaemia (WM) was made. Computerized tomography of the brain showed a butterfly-shaped hyperdensity in the splenium of the corpus callosum, with ventricular dilatation. Magnetic resonance imaging displayed high-intensity signals on T2-weighted sequences. Protein immunoelectrophoresis elicited an IgM kappa peak. The CSF was found to contain proteins and lymphocytes in excess, and immunohistochemical staining confirmed the predominance of anti-kappa and the presence of intrathecal IgM secretion. Chemotherapy was temporarily effective on the memory disorders, but the patient died 26 months after the beginning of treatment. Central nervous system manifestations are seldom observed in WM, and they are now grouped under the name of Bing-Neel syndrome. Psychic disorders are rarely reported. It is suggested that IgM secretion plays a predominant role in the pathogenesis of leucoencephalitis, and this is supported by the finding of intrathecal IgM synthesis.

Visual evoked potentials in patients with neuropathy and macroglobulinemia.

Visual evoked potentials were studied in 11 patients with neuropathy and macroglobulinemia. The P100 latency was increased bilaterally in 5 of the 6 patients whose IgM M-proteins reacted with myelin-associated glycoprotein (MAG) and in 1 of the other patients. In patients whose M-protein bound to MAG, abnormal visual evoked potentials correlated with the presence of the M-protein in the cerebrospinal fluid. Subclinical involvement of the central nervous system is frequent in patients with neuropathy and anti-MAG M-proteins and may be due to the binding of M-proteins to central nervous system myelin.

Cerebrospinal fluid monoclonal gammopathy in multiple myeloma and Waldenström's macroglobulinemia.

Serum ratios of monoclonal immunoglobulin (Ig) to total protein, monoclonal immunoglobulin to albumin, CSF/serum Ig-albumin index, and CSF to serum monoclonal immunoglobulin were obtained in 21 patients with multiple myeloma and 2 with Waldenström's macroglobulinemia. Twelve patients (3 with CNS complications) showed CSF monoclonal proteins similar to their serum. CSF IgA levels above 10 mg/dl, IgG levels above 25 mg/dl, CSF-serum IgG ratios above 0.0034 and CSF-serum IgA ratios above 0.0051 were seen in patients with neurologic complications. Our preliminary data may signal early CNS involvement in multiple myeloma.