Matthew Maeder MD Jane Lee MD Dana Shani MD Bidyut Pramanik MD Diagnostic Challenge in a Case of Bing Neel Syndrome with Orbital Involvement Imaging Findings Before and After Treatment Matthew Maeder MD Jane Lee MD Dana Shani MD Bidyut Pramanik MD

The authors have nothing to disclose

Case presentation 65-year-old Caucasian female History of hypertension, Non Hodgkins Lymphoma (NHL) treated 10 years ago, and Waldenström Macroglobulinemia (WM) Presented with acute onset of expressive aphasia for 6 hours Chronic headaches and chronic blurry vision in right eye Unsteady gait, “veering to the left”

Initial CT Head No significant findings

FLAIR: Minimum nonspecific white matter disease Initial MRI Brain FLAIR: Minimum nonspecific white matter disease

Diffusion-weighted imaging: No acute ischemia Initial MRI Brain Diffusion-weighted imaging: No acute ischemia DWI ADC map

Pre-contrast T1 Post-contrast T1 Initial MRI Brain Post contrast T1: Minimum linear and nodular enhancement in bilateral internal auditory canals initial mri min WM disease no acute ischemia post contrast images demo minimum linear and nodular enha in b IACs Pre-contrast T1 Post-contrast T1

Initial MRI Brain Summary: Minimum nonspecific white matter disease, no acute ischemia, abnormal enhancement in the IACs Impression: No acute ischemia. Abnormal enhancement in the IACs suspicious for leptomeningeal disease.

Lumbar Puncture Cytopathology Results: Consistent with CNS involvement by a CD10 positive low-grade B cell lymphoma Cytopathology Addendum Report   Addendum INTERPRETATION FLOW CYTOMETRY ANALYSIS FOR LYMPHOPROLIFERATIVE DISORDERS COMMENT Involvement by CD10+ B-cell lymphoma. subset of large B-cell lymphoma and Burkitt's lymphoma. Phenotypically, the possibilities include follicular lymphoma, a physiochemical analysis and other clinical parameters suggested. lymphoma diagnosis?), image study of the brain, cytology, Correlation with patient's past medical history (any confirmed GROSS DESCRIPTION prepared for Flow Cytometry. A cytocentrifuge preparation is Received colorless fluid measuring 3 cc. in volume. The fluid is iMS stained with Wright-Giemsa. 7AAD: 96% Percentage of Abnormal Cells: 27% Cell Size: Small Viability IMMUNOPHENOTYPIC ANALYSIS A monoclonal kappa, CD10 positive B-cell population is present. B-Cell Associated Activation Antibody Description Result Antibody Description Result RESULTS B, myeloid Positive, CD19 Pan B-cell antigen Positive, Moderate CD38 Activated T, CD10 Follicle center B-cells, CALLA, Positive, Moderate Anchor B-cell subset Moderate CD20 Pan B-cell antigen Positive, Moderate cells, CD45 Leukocyte common Positive, myeloid subset antigen Moderate cell leukemia CD11c Monocytes, myeloid subset, hairy Negative FMC-7 B-Cell associated antigen in B- Negative  CD23 Mature B-cells, CLL Negative Cell subset plasma cells Kappa Kappa Ig light chain, B-cells, Positive, Moderate Lambda Lambda Ig light chain, B-cells, Negative CD2 Thymic and peripheral T-cells, NK Negative T-Cell Associated Antibody Description Result cells subunit CD3 Pan T-cell antigen, TCR-epsilon Negative CD4 Helper T-cells, thymocyte subset, Negative monocytes (B1a cells) CD5 Pan T-cells, mature B-cell subset Negative CD7 Thymic and peripheral T-cells, NK Negative CD8 Suppressor T-cells, NK cells, Negative thymocyte subset CD57 T-cell subset, NK cells Negative CD56 T-cell subset, NK cells Negative a specialized BioReference Laboratory. Testing has been performed Lymphoproliferative Disorders, reported on 07/10/2014 by GenPath, This addendum reports the results of Flow Cytometry Analysis for Hospital specimen 75-NG-14-1668, with GenPath ID: 302582680. Elmwood Park, NJ 07470, phone: 1-800-627-1479, on Lenox Hill at BioReference Laboratories, Inc., 481 Edward H. Ross Drive, Please refer to the official GenPath report, which is on file in  the Pathology Department. Ryan DesJean, M.D. Reported on: 07/11/14 (Electronic Signature) Cytopathology Report CEREBROSPINAL FLUID Specimen(s) Submitted Clinical History Waldenstroms macroglobulinemia Gross Description 2 cytospins 3 cc. clear fluid Satisfactory for interpretation. Statement of Adequacy CEREBROSPINAL FLUID: Final Diagnosis SIGNIFICANT FINDINGS. specimen is sent for flow cytometry which reveals a CD10 positive some showing a plasmacytoid morphology. A portion of the Examination of this specimen reveals abundant small lymphocytes, cytometry is consistent with CNS involvement by a CD10 positive morphology of this lymphoid infiltrate combined with the flow B cell lymphoma (see addendum for further details). The Bonomo and Dr. Shani on 7/11/2014. low-grade B cell lymphoma. These results are discussed withDr. Ami Fujii Yeh, CT(ASCP) ________________________________________________________________

Diagnosis: Bing Neel Syndrome WM is a lymphoplasmacytic lymphoma When it involves the CNS it is called Bing Neel Syndrome Few reported cases of CNS or orbital involvement Our case is unusual because it involves both CNS & orbital structures The reported imaging findings of BNS is nonspecific. Our case demonstrates the diagnostic dilemma, with multifocal areas of FLAIR signal abnl and enhancement

Diagnosis: Bing Neel Syndrome The white matter lesions and pattern of enhancement are nonspecific; MRI findings shown are typical and demonstrate the diagnostic difficulty There are no established treatment guidelines for this disease The reported imaging findings of BNS is nonspecific. Our case demonstrates the diagnostic dilemma, with multifocal areas of FLAIR signal abnl and enhancement

Treatment The patient began chemotherapy week 1, soon after presentation Systemic chemotherapy was given every 4 weeks Rituximab 375 mg/m2 Bendamustine 90 mg/m2 Intrathecal chemotherapy was given via Ommaya reservoir Methotrexate 15 mg twice weekly for 3 months Started on 9/2 ~week 8? Until 10/30 Started after second MR….

Clinical Picture CSF cytology and flow cytometry at week 10 no longer identified a monoclonal B-cell population of cells Aphasia had resolved but there was persistent blurry right eye vision and new onset right eye lateral gaze deviation *Was there any hearing or vision symptoms?

Follow Up MRI (Week 8) Now demonstrates confluent FLAIR signal abnormalities in the midbrain, pons, optic chiasm and tracts, periventricular white matter and the corpus callosum What happened for 7 weeks? E.g. patient was followed closely observed symptoms for 6 wks All Subsequent MRI demo improvaeent enh in IAC, however interval dev of subependymal enhancement lining vents esp front horns, diffuse infilt of the retrobulb fat with enh, IMP: Extensive prog of signal abnl and enhancement FLAIR conflu signal abn along the head of caudate (ax 20), bilateral perifrontal ependymal (1201:14), splenium. FLAIR midb/pons optic chiasm and tracts (ax 16), ax 14. Intrapeduncular cistern (post C 16) (8), orbits (ax 7) and (cor 11), STIR (cor 11) preT1 (cor 9). Post 19, Summary slide of images

Follow Up MRI (Week 8) Development of new multifocal areas of nodular and subependymal enhancement All Subsequent MRI demo improvaeent enh in IAC, however interval dev of subependymal enhancement lining vents esp front horns, diffuse infilt of the retrobulb fat with enh, IMP: Extensive prog of signal abnl and enhancement FLAIR conflu signal abn along the head of caudate (ax 20), bilateral perifrontal ependymal (1201:14), splenium. FLAIR midb/pons optic chiasm and tracts (ax 16), ax 14. Intrapeduncular cistern (post C 16) (8), orbits (ax 7) and (cor 11), STIR (cor 11) preT1 (cor 9). Post 19, Summary slide of images Post-contrast T1

However, there was improvement in enhancement in bilateral IACs Follow Up MRI (Week 8) However, there was improvement in enhancement in bilateral IACs All Subsequent MRI demo improvaeent enh in IAC, however interval dev of subependymal enhancement lining vents esp front horns, diffuse infilt of the retrobulb fat with enh, IMP: Extensive prog of signal abnl and enhancement FLAIR conflu signal abn along the head of caudate (ax 20), bilateral perifrontal ependymal (1201:14), splenium. FLAIR midb/pons optic chiasm and tracts (ax 16), ax 14. Intrapeduncular cistern (post C 16) (8), orbits (ax 7) and (cor 11), STIR (cor 11) preT1 (cor 9). Post 19, Summary slide of images Post-contrast T1

MRI (Week 8) Dedicated orbital imaging: Diffuse infiltration of the retrobulbar fat with enhancing soft tissue All Subsequent MRI demo improvaeent enh in IAC, however interval dev of subependymal enhancement lining vents esp front horns, diffuse infilt of the retrobulb fat with enh, IMP: Extensive prog of signal abnl and enhancement FLAIR conflu signal abn along the head of caudate (ax 20), bilateral perifrontal ependymal (1201:14), splenium. FLAIR midb/pons optic chiasm and tracts (ax 16), ax 14. Intrapeduncular cistern (post C 16) (8), orbits (ax 7) and (cor 11), STIR (cor 11) preT1 (cor 9). Post 19, Summary slide of images Post-contrast T1 fat-suppressed STIR Pre-contrast T1

MRI (Week 8) Summary of corresponding brain images: Extensive progression of FLAIR signal abnormalities and enhancement Week 1 Week 8 All Subsequent MRI demo improvaeent enh in IAC, however interval dev of subependymal enhancement lining vents esp front horns, diffuse infilt of the retrobulb fat with enh, IMP: Extensive prog of signal abnl and enhancement FLAIR conflu signal abn along the head of caudate (ax 20), bilateral perifrontal ependymal (1201:14), splenium. FLAIR midb/pons optic chiasm and tracts (ax 16), ax 14. Intrapeduncular cistern (post C 16) (8), orbits (ax 7) and (cor 11), STIR (cor 11) preT1 (cor 9). Post 19, Summary slide of images

Clinical Picture The patient continued chemotherapy and continued to gradually improve An MRI was ordered to evaluate new right eye ptosis *Was there any hearing or vision symptoms?

MRI 13 weeks after start of chemotherapy (Week 14) Improved subependymal enhancement All findings obtained X weeks / months after treatment. Orbits 10/7: 1101:12 decreased enh interpedunclar cistern Cor 1001:9 10/5: 11:16 FLAIR 14 + 18 “The brain involvement has dramatically improved The response in the orbits was some, still significant disease Summary slide of images Week 8 Week 14

MRI 13 weeks after start of chemotherapy (Week 14) Improved enhancement in interpeduncular cistern All findings obtained X weeks / months after treatment. Orbits 10/7: 1101:12 decreased enh interpedunclar cistern Cor 1001:9 10/5: 11:16 FLAIR 14 + 18 “The brain involvement has dramatically improved The response in the orbits was some, still significant disease Summary slide of images Week 8 Week 14

MRI 13 weeks after start of chemotherapy (Week 14) Mild improvement in infiltration of the retrobulbar fat and enhancing orbital soft tissues Week 8 Week 14 All findings obtained X weeks / months after treatment. Orbits 10/7: 1101:12 decreased enh interpedunclar cistern Cor 1001:9 10/5: 11:16 FLAIR 14 + 18 “The brain involvement has dramatically improved The response in the orbits was some, still significant disease Summary slide of images

MRI (Week 14) Summary: The brain involvement responded to therapy. However, significant disease still remained in the orbits. All findings obtained X weeks / months after treatment. Orbits 10/7: 1101:12 decreased enh interpedunclar cistern Cor 1001:9 10/5: 11:16 FLAIR 14 + 18 “The brain involvement has dramatically improved The response in the orbits was some, still significant disease Summary slide of images

What exactly can happen in the CNS? Commonly, WM causes CNS symptoms due to hyperviscosity of blood More rarely, there is direct invasion by the malignant cells in WM Lymphocytes, plasma cells Appearance of invasion is divided into diffuse or tumoral forms 2,5

MRI Features of Bing Neel in the CNS T2 and FLAIR: Hyperintensity is typical Typical locations are pons, medulla, periventricular white matter, leptomeninges 2,3,5 Contrast enhancement: Some cases have associated foci of enhancement within the T2/FLAIR hyperintense regions 2,3 DWI: Few case reports describe scattered foci of diffusion restriction in different arterial territories 4

MRI Features of Bing Neel in the Orbit Few reports of orbital involvement describe infiltration of the optic nerve, retrobulbar fat, and extraocular muscles 5 Infiltration consists of fat-suppressed T2 hyperintensity, enhancement, or both Infiltration of retrobulbar fat may lead to proptosis

Conclusion Bing Neel Syndrome is rare, and should be considered when given a history of Waldenström Macroglobulinemia MRI Brain may show T2/FLAIR hyperintensity, sometimes with associated foci of enhancement Imaging findings may worsen during treatment Evaluate the orbits for retrobulbar fat infiltration and proptosis

References Cuenca HR, Guzman DVLJ, Roa ME, et al. Bing-Neel syndrome as an initial sign of Waldenström macroglobulinaemia associated with orbital infiltration. Neurologia (Barcelona, Spain) (2013) Kim HJ, Suh SI, Kim JH, et al. Brain magnetic resolution imaging to diagnose bing-neel syndrome. Journal of Korean Neurosurgical Society 46.6 (2009): 588-591 Van Cauwenberge MG, Depreter B, Dumoulin EN, et al. Bing–Neel syndrome: Two unexpected cases and a review of the literature. Journal of the neurological sciences 356.1 (2015): 19-26 Arias M, Pereiro Zabala I, Requena Caballero I, et al. [Rapidly progressing dementia as the presenting symptom of Waldenström’s macroglobulinemia : findings from magnetic resonance imaging of the brain in Bing Neel syndrome.] Rev Neurol 38 : 640-642, 2004 Stacy RC, Jakobiec FA, Hochberg FH, et al. Orbital involvement in bing-neel syndrome. Journal of Neuro-Ophthalmology 30.3 (2010): 255-259