The absence of standardized approaches for the management of patients with Bing-Neel syndrome was a central theme of a literature review, published in the British Journal of Haematology, that covered the diagnosis and treatment of patients with this condition.1

Waldenström macroglobulinemia (WM) is a “lymphoplasmacytic lymphoma in which the malignant cells produce a monoclonal IgM paraprotein,” and clinical manifestations of the disease can include anemia, and IgM-related hyperviscosity and peripheral neuropathy.

While WM is a rare disorder, with an estimated incidence in the US of 5 per 1,000,000 people over the age of 50 years,2 Bing-Neel syndrome, an extramedullary manifestation of WM involving the central nervous system (CNS), is observed in approximately 1% of patients diagnosed with this disease.

Interestingly, although Bing-Neel syndrome was first reported 6 years prior to the seminal report of WM, diagnosis of this condition is “sometimes elusive and its management has not been standardized,” noted the authors.

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The main aim of this review was to summarize both the clinical and pathological criteria used in the diagnosis of Bing-Neel syndrome, as well as approaches to the treatment and monitoring of patients with this condition.

One specific diagnostic challenge mentioned by the authors was distinguishing Bing-Neel syndrome from symptoms of IgM-related hyperviscosity and immune peripheral neuropathy more commonly associated with WM, with the caveat that coexistence of these 2 manifestations of the disease is possible. 

While bilateral, symmetrical sensory deficits affecting the limbs were cited as more characteristic of WM-related peripheral neuropathy, asymmetrical peripheral neuropathy with predominantly motor deficits, as well as progressive headaches and cognitive deficits, were mentioned as disease manifestations that should raise clinical suspicion for Bing-Neel syndrome.

Magnetic resonance imaging (MRI) of the brain and entire spine with gadolinium administration was recommended by the authors for patients with suspected Bing-Neel syndrome.

However “despite the usefulness of MRI in BNS [Bing-Neel syndrome] diagnosis, there is not one radiological finding pathognomonic of BNS,” the authors noted, hence, lumbar puncture or biopsy of brain tissue is also necessary to assess for the presence of clonal lymphoplasmacytic cells in the cerebrospinal fluid or CNS. Furthermore, detection of IGH rearrangements and the MYD88 L265P mutation have been reported to be present in 94% and 100% of patients with Bing-Neel syndrome, respectively.

The authors recommended CNS-penetrating treatment approaches in all patients with symptomatic Bing-Neel syndrome. Specifically, based on available evidence, first-line treatment with the Bruton tyrosine kinase (BTK) inhibitor, ibrutinib, was recommended for patients not previously exposed to this agent, followed by fludarabine, bendamustine, cladribine, high-dose methotrexate, or high-dose cytarabine for those with relapsed disease.

Proteasome inhibitors, novel BTK inhibitors, and the BCL2 antagonist, venetoclax, were also mentioned as potential future approaches for the treatment of patients with Bing-Neel syndrome.

In their concluding remarks, the authors commented that “Bing-Neel syndrome patients are typically excluded from prospective clinical trials and given the rarity of Bing-Neel syndrome, prospective therapeutic studies will only be possible through multi-institutional efforts.”

References

  1. Castillo JJTreon SP. How we manage Bing-Neel syndrome [published online August 20, 2019]. Br J Haematol. doi: 10.1111/bjh.16167
  2. National Organization for Rare Disorders. Rare disease database: Waldenström macroglobulinemia. Accessed September 16, 2019.