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\begin{document}

\title{Diagnosing, Imaging and Successfully Treating a Debilitating Case of
Bing-Neel Syndrome: A Multidisciplinary Feat.}



\author[1]{Robert Kerley}%
\author[2]{Niamh O’Donnell}%
\author[2]{Fiona Lynott}%
\author[2]{Riona Mulcahy}%
\author[2]{Brian Hennessy}%
\affil[1]{Cork University Hospital}%
\affil[2]{University Hospital Waterford}%


\vspace{-1em}



  
  \date{May 25, 2024}


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\selectlanguage{english}
\begin{abstract}
Here we present a diagnostically challenging Bing-Neel Syndrome (BNS)
case successfully treated with systemic chemoimmunotherapy and
ibrutinib, with remarkable clinical response. BNS is an extremely rare
direct central nervous system infiltration by malignant
lymphoplasmocytic lymphoma cells in patients with Waldenstroms
macroglobulinaemia.%
\end{abstract}%



\sloppy


\textbf{Title} :

Diagnosing, Imaging and Successfully Treating a Debilitating Case of
Bing-Neel Syndrome: A Multidisciplinary Feat.

\textbf{Corresponding Authors} : Robert N. Kerley\textsuperscript{1,2}

\textbf{Email} : r.kerley@umail.ucc.ie

\textbf{Authors} :

Niamh O'Donnell\textsuperscript{2}

Fiona Lynott\textsuperscript{2}

Riona Mulcahy\textsuperscript{2}

Brian Hennessy\textsuperscript{2}

1 Cork University Hospital, Wilton, Cork, Ireland

2 University Hospital Waterford, Dunmore Road, Waterford, Ireland

No conflicts of interest to declare

Written informed consent was obtained from the patient to publish this
report in accordance with the journal's patient consent policy.

\textbf{Keywords} :

Bing-Neel Syndrome, Waldenstroms Macroglobulinaemia.



\textbf{Diagnosing, Imaging and Successfully Treating a Debilitating
Case of Bing-Neel Syndrome: A Multidisciplinary Feat.}

Waldenstroms macroglobulinaemia (WM) is a rare B-cell lymphoma
representing \textasciitilde{}2\% of all haematological malignancies.
While most neurological complications of WM are secondary to the
overproduction of immunoglobulin M (IgM), Bing-Neel syndrome (BNS) is an
extremely rare direct central nervous system (CNS) infiltration by
malignant lymphoplasmocytic lymphoma (LPL) cells. Limited information on
BNS exists in the literature with sparse case reports and case series.
Here we present a diagnostically challenging BNS case successfully
treated with systemic chemoimmunotherapy and ibrutinib, with remarkable
clinical response.

\textbf{1. Initial Presentation}

A 63-year-old lady presented to the Emergency Department (ED) with a
one-day history of binocular diplopia and evidence of abducens nerve
palsy on examination. Medical history included dyslipidaemia,
non-alcoholic fatty liver disease (NASH) and colonic poly removal.
Visual symptoms occurred gradually over weeks without diurnal variation.
Fundal examination was unremarkable. Admission bloods, chest x-ray and
CT brain did not reveal a cause for the patient's neurological symptoms.
Full blood count showed a haemoglobin (Hb) of 10.6 g/dL but was
otherwise unremarkable. Her vasculitic, viral, and lyme serology screen
were negative. Incidentally, her serum protein electrophoresis showed an
IgM paraproteinemia, with a paraprotein level of 4.2 g/L. Renal
function, serum calcium, beta-2-micorglobulin and plasma viscosity
levels were within normal ranges. An MRI Brain, orbits and cervical cord
revealed significant cervical spondylosis with multi-level nerve root
impingement. Lumbar puncture (LP) showed raised cerebrospinal fluid
(CSF) protein (0.97 g/dL) and leukocyte count (31 x
10\textsuperscript{9}/L, 90\% lymphocytes, 10\% polymorphs). She was
discharged with an incidental diagnosis of monoclonal gammopathy of
undetermined significance (MGUS) with close follow from neurology and
general medicine.

\textbf{2. Progression and Diagnosis}

Two weeks later the patient was re-admitted with ataxia, gait
disturbance and loss of power bilaterally in her lower limbs. On
examination, power was 3/5 in both lower limbs and 5/5 in her upper
limbs. Tone was normal, sensation and reflexes were intact without
evidence of coordination deficits and an extensor plantar reflex. A
repeat MRI Brain and whole spine with contrast was negative for
leptomeningeal or parenchymal enhancement. Without a diagnosis and
progressive neurological deficits, a broader differential was conducted
to include nerve conduction studies, a repeat autoimmune, vasculitic and
viral screen, CT thorax, abdomen \& pelvis, and serum ACE all of which
were non-diagnostic. Finally, a repeat LP with CSF immunophenotyping and
second MRI whole spine with contrast were ordered to exclude
infiltrative disease (Figure 1). This MRI result was discussed at three
major neuroradiology sites in our country to form a consensus on the
presence of infiltrative disease. Subtle posterior meningeal enhancement
involving the distal cord at T10 and T11 vertebral bodies was observed.
In the context of macroglobulinaemia, a bone marrow biopsy was performed
which showed a normocellular specimen with no evidence of lymphomatous
infiltration. While awaiting her CSF sample to return from flow
cytometry she deteriorated with ascending paralysis compromising
respiratory drive and requiring transfer to the intensive care unit
(ICU). The following morning, CSF immunphenotyping revealed a clonal
population of kappa light chains restricted B cells, which were CD5 and
CD10 negative, consistent with CNS involvement by lymphoma, in keeping
with a diagnosis of BNS.

\textbf{3. Treatment}

Prior to diagnosis, IV Methylprednisolone 1g was given for three days
with a partial subjective response to limb paralysis but no response as
regards her abducens nerve palsy. Following CSF analysis, a combination
of chemo- and immunotherapy with intrathecal (IT) Methotrexate (MTX),
subcutaneous Rituximab and pulsed oral dexamethasone were urgently
commenced. Twenty-four hours post IT-MTX, Ibrutinib 420mg PO OD was
introduced. Due to the patient's neurological deficits and difficulty
performing LPs, as well as reluctance to interrupt ibrutinib for LPs, a
decision was made to switch from IT-MTX to high dose IV MTX (3.5g/m2)
for second and third cycles. In total the patient received the following
induction therapy: one IT MTX, two cycles of high dose IV MTX, weekly
rituximab for four weeks, four pulses of oral dexamethasone (40mg
fortnightly) and oral ibrutinib. This treatment was well-tolerated. A
repeat CSF sample was sent for flow cytometry post the above treatment
with no clonal population of B cells detected. In addition, the
patient's neurological symptoms responded over weeks from 1/5 power to
4/5 power in her lower limbs. As per the 2014 task force guidelines on
BNS these CSF findings in conjunction with the resolution of symptoms
suggests a clinical response in keeping with complete remission {[}1{]}.
The patient received two further doses of subcutaneous rituximab
monthly. She currently remains on oral ibrutinib, with a plan to
continue this for at least two years.

\textbf{4. Discussion}

The clinical presentation of BNS as shown in this case is diverse and
non-specific. A critical point that could explain the under recognition
of BNS is its frequent occurrence independent of any systemic
progression of WM, with up to one-third of BNS cases coinciding with
diagnosis of WM {[}2, 3{]}. Radiological assessment was critical to the
diagnosis in this case requiring input from experienced
neuroradiologists. In a case series of 24 patients the most common MRI
finding was leptomeningeal infiltration either intracranial or spinal
with a prevalence reaching 70.8\% {[}4{]}. Dural and parenchymal
involvement were present in 37.5\% and 41.7\% of patients, respectively.
Autopsy results have observed more extensive meningeal and perivascular
infiltration by malignant cells than that revealed by MRI {[}5{]}. the
gold standard for diagnosis is a histological biopsy of the affected
area or CSF analysis by flow cytometry demonstrating malignant cells as
previously outlined {[}1{]}.

There is no established treatment regimen for BNS to date. Patients
typically receive a combination of systemic and IT chemotherapy,
immunotherapy, and novel agents, such as ibrutintib, an oral Bruton
kinase inhibitor. The goal of treatment should be to (1) reverse the
patient's clinical symptoms and (2) induce prolonged progression-free
survival {[}6{]}. Remission has been reported with both IT therapies
and/or systemic chemotherapies {[}1, 2, 7, 8{]}. Use of high-dose MTX is
extrapolated from data in primary CNS lymphoma while direct evidence
supports the use of Rituximab in BNS {[}3, 9{]}. Ibrutinib, has been
increasingly employed in BNS treatment, as well as other primary CNS
lymphomas {[}10-12{]}. Data suggests ibrutinib maintenance also has a
role in prolonging progression-free survival rationalising its use in
our patient's case {[}13{]}. In one review of 34 patients with BNS, the
estimated overall survival rate at 3 years was 59\% {[}14{]}. Age
\textgreater{} 65 years, thrombocytopenia and previous treatment for WM
were all associated with worse prognosis {[}14{]}. Our patient has none
of these characteristics and remains in complete remission 6 months post
diagnosis.

\textbf{References}

1. Minnema MC, Kimby E, D'Sa S, Fornecker L-M, Poulain S, Snijders TJ,
et al. Guideline for the diagnosis, treatment and response criteria for
Bing-Neel syndrome. Haematologica. 2017;102(1):43-51.

2. Varettoni M, Defrancesco I, Diamanti L, Marchioni E, Farina LM,
Pichiecchio A. Bing-Neel Syndrome: Illustrative Cases and Comprehensive
Review of the Literature. Mediterranean journal of hematology and
infectious diseases. 2017;9(1):e2017061-e.

3. Simon L, Fitsiori A, Lemal R, Dupuis J, Carpentier B, Boudin L, et
al. Bing-Neel syndrome, a rare complication of Waldenstr\selectlanguage{ngerman}öm
macroglobulinemia: analysis of 44 cases and review of the literature. A
study on behalf of the French Innovative Leukemia Organization (FILO).
Haematologica. 2015;100(12):1587-94.

4. Fitsiori A, Fornecker LM, Simon L, Karentzos A, Galanaud D, Outteryck
O, et al. Imaging spectrum of Bing-Neel syndrome: how can a radiologist
recognise this rare neurological complication of Waldenström's
macroglobulinemia? Eur Radiol. 2019;29(1):102-14.

5. Matsuda S, Sekiguchi N, Ito K, Takaoka K, Furuki M, Hirano K, et al.
An Autopsy Case of Bing-Neel Syndrome: Discrepancy between the
Radiological and Pathological Findings. Intern Med. 2019;58(13):1947-51.

6. Castillo JJ, Treon SP. How we manage Bing--Neel syndrome. British
Journal of Haematology. 2019;187(3):277-85.

7. Nagaharu K, Miyazami K, Imai H, Tamura A, Umino A, Fujieda A, et al.
{[}Successful treatment of Bing-Neel syndrome using combination therapy
with fludarabine and rituximab{]}. Rinsho Ketsueki. 2014;55(12):2423-8.

8. Gavriatopoulou M, Ntanasis-Stathopoulos I, Moulopoulos LA, Manaios A,
Fotiou D, Eleutherakis-Papaiakovou E, et al. Treatment of Bing-Neel
syndrome with first line sequential chemoimmunotherapy: A case report.
Medicine (Baltimore). 2019;98(44):e17794.

9. Poulain S, Boyle EM, Roumier C, Demarquette H, Wemeau M, Geffroy S,
et al. MYD88 L265P mutation contributes to the diagnosis of Bing Neel
syndrome. Br J Haematol. 2014;167(4):506-13.

10. Bernard S, Goldwirt L, Amorim S, Brice P, Brière J, de Kerviler E,
et al. Activity of ibrutinib in mantle cell lymphoma patients with
central nervous system relapse. Blood. 2015;126(14):1695-8.

11. Chamoun K, Choquet S, Boyle E, Houillier C, Larrieu-Ciron D, Al
Jijakli A, et al. Ibrutinib monotherapy in relapsed/refractory CNS
lymphoma: A retrospective case series. Neurology. 2017;88(1):101-2.

12. Cabannes-Hamy A, Lemal R, Goldwirt L, Poulain S, Amorim S, Pérignon
R, et al. Efficacy of ibrutinib in the treatment of Bing--Neel syndrome.
American Journal of Hematology. 2016;91(3):E17-E9.

13. O'Neil DS, Francescone MA, Khan K, Alobeid B, Bachir A, O'Connor OA,
et al. A Case of Bing-Neel Syndrome Successfully Treated with Ibrutinib.
Case reports in hematology. 2018;2018:8573105-.

14. Castillo JJ, D'Sa S, Lunn MP, Minnema MC, Tedeschi A, Lansigan F, et
al. Central nervous system involvement by Waldenström macroglobulinaemia
(Bing-Neel syndrome): a multi-institutional retrospective study. Br J
Haematol. 2016;172(5):709-15.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

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\end{figure}

\textbf{Figure 1 MRI whole spine outlining subtle posterior meningeal
enhancement at T10 and T11.}

\selectlanguage{english}
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