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Bing-Neel Syndrome

• Introduction of the disease

History

It was first described in 1936 by Jens Bing and Axel Valdemar Neel, who observed a case of 2 women, 56 and 39 years old, presenting with rapid neurodegeneration in the setting of hyperglobulinemia. This discovery was reported eight years before the first report on Waldenström macroglobulinemia (WM), which was discovered and described by Jan Waldenström. From the first publication, there was never a clear consensus and guideline to the diagnosis and treatment of BNS. It was only 80 years later that there was a meeting with a group of people at the 8th International Workshop on Waldenström macroglobulinemia. These group of people included radiologists, immunologists, hematologists, and neurologists from all over the world using PubMed as their source for the guideline. The first draft was reviewed by a multidisciplinary team of experts on Waldenström macroglobulinemia. Ever since the first case report on Bing-Neel Syndrome, there has been many more cases, at least a hundred, that reports people with the diagnosis of BNS.

Symptoms

Symptoms of Bing-Neel Syndrome gradually progress over the span of a week or even a month. Although Bing-Neel Syndrome arises due to complications from Waldenström macroglobulinemia (WM), some individuals may experience symptoms of Bing-Neel Syndrome without having a past history of (WM).

Given that Bing-Neel Syndrome is so rare, the symptoms are diverse and nonspecific. Symptoms range in severity from nausea to seizures and are characterized by nausea and vomiting, visual disturbance, hearing loss and cranial neuropathies (predominantly in oculomotor nerves), meningeal involvement, cognitive decline (such as memory lose), aphasia or a lose of language function , some form of psychosis, cerebellar dysfunction (uncontrolled movement and lose of balance) , impaired consciousness (coma), paresis (muscle weakness). Some sensory symptoms, include a pin and needles sensation in the hands, arms, legs or feet, pain and extreme numbness. Some symptoms also include periods of confusion, slurred speech, headache, and fatigue.

Where certain symptoms are present depends on which branch of the CNS is being affected.

Diagnosis

There is no clear-cut route to diagnosing Bing-Neel Syndrome(BNS), meaning no one diagnostic tool alone is conclusive in diagnosing BNS. But through the utilization of several different tools cooperatively, a diagnosis can be reached through the elimination of other CNS pathologies.

Histology

Infiltration of malignant, differentiated B-cells linked to Waldenstrom Macroglobulinemia (WM) into the nervous system precipitates Bing-Neel Syndrome (BNS). Histological practices that entail a biopsy of the cerebrum and/or the meninges look for the presence of lymphoplasmacytic lymphomas (Mature B-cells). Though a biopsy alone is not indicative of BNS, it is a necessary step that ensures that at the very least, the CNS has been infiltrated by some sort of lymphoma.

Cerebrospinal Fluid Analysis

Analysis entails analyzing several different aspects of the cerebrospinal fluid (CSF) to identify characteristics linked to WM and BNS. Quantification of leukocytes and their differentiation as well as a morphological analysis of any detected malignant lymphomas found in the CSF.

Flow cytometry, used to identify cell biomarkers, is an auxiliary tool used in CSF analysis. With respect to diagnosing BNS, flow cytometry analyzes CSF contents for B-cells expressing the pan antigens CD19 and CD20, commonly found in WM; it should be noted, not all cases of BNS show conclusive findings in CSF analysis.

Radiology

MRI with gadolinium contrast is the primary radiologic tool used to diagnose ailments of the central nervous system, BNS included. MRI’s effect is twofold in that it is able to identify brain and spine abnormalities, as well as identifying tissues appropriate for biopsy. MRI with gadolinium contrast can also discern which form of BNS has formed. Where the tumoral form of BNS is highlighted by tumor growth in the subcortical hemispheric regions, the diffuse form of BNS is characterized by leptomeningeal and perivascular infiltration by lymphoid cells. Other characteristics of BNS identified via MRI are abnormal enhancement of cranial and spinal nerves, as well as thickening and enhancement of the cauda equina.

Sequence Analysis

The MYD88 L2659 is a gene mutation found in the majority of WM cases. During CSF analysis, PCR amplification of genomic DNA found in the fluid followed by sequencing can determine if the mutation is present within the CNS; is so, this would be indicative of, though not conclusive, of BNS.

Treatment

            Treatment for Bing-Neel Syndrome (BNS) typically follows a certain path with a multitude of options. . If patients with BNS are asymptomatic, physicians will watch for progression of the disease using MRI. If any signs of further disease is shown, they will take action to alleviate the symptoms. Because this disease is non-curative, treatment is only used to get rid of symptoms that are ailing the patient. Even so, due to the lack of regeneration of the nervous system some symptoms may not be reversible and stay with the patient. There are some costs along with the benefits of treating symptoms depending on the type. They may include lesions or brain damage. Doctors will make sure to monitor the patient by MRI to make sure these complications do not occur.

There are a few options when it comes to treatment so the type one will choose is completely individualized, taking into consideration the patient’s state or condition and liking. Three very useful components include steroids, chemotherapy, and radiation.

Steroids

Steroids are mostly used for short term and quick use. It provides improvement, but should not be considered a long term plan. Physicians would normally prescribe these after a biopsy and further analysis has been completed.

Chemotherapy

Treatment also involves central nervous system penetrating chemotherapy. Options include intrathecal, intraventricular, and systemic chemotherapy. These must penetrate the blood-brain barrier in order to be effective. Sometimes mixing multiple forms of treatment with chemotherapy seems to be the best route. For example, some significant improvement has been shown in patients as a result of cranial radiation treatment preceding a brief course of intrathecal chemotherapy.^[6] In Arkansas, a patient was treated with "intrathecal chemotherapy with several cycles of systemic chemotherapy followed by autologous stem cell-supported high-dose therapy transplant. The patient discontinued all treatment in 2009 and was still asymptomatic by the time a follow-up report was published in 2013.^[7]” Although this is an effective treatment to do, penetrating the blood-brain barrier can cause side effects due to the toxicity in the nervous system. These would include dizziness, confusion, and changes in mental status. Another form could be the use of pharmaceuticals such as Fludarabine, Cladribine, Bendamustine, and Ibrutinib, which have all shown positive effects for treatment.

Radiation     

Lastly radiation is normally used as a rescue type treatment and is not recommended as a first line treatment. The doctor would perform localized radiation therapy at a dose of 30 to 40 Gy, on the lesions in the patient. This is to limit the amount of radiation and prevent further damage to the nervous system which could happen due to the toxicity of radiation therapy.

References

Monique C. Minnema, Eva Kimby, Shirley D’Sa, Luc-Matthieu Fornecker, Stéphanie Poulain, Tom J. Snijders, Efstathios Kastritis, Stéphane Kremer, Aikaterini Fitsiori, Laurence Simon, Frédéric Davi, Michael Lunn, Jorge J. Castillo, Christopher J. Patterson, Magali Le Garff-Tavernier, Myrto Costopoulos, Véronique Leblond, Marie-José Kersten, Meletios A. Dimopoulos, Steven P. Treon Haematologica Jan 2017, 102 (1) 43-51; DOI: 10.3324/haematol.2016.147728 http://www.haematologica.org/content/102/1/43