Supplementary Table 2 Cases of CNS involvement by Waldenstrom’s macroglobulinemia (‘Bing–Neel Syndrome’).
References
Age/ Clinical syndrome Autopsy findings
sex
Aarseth et al. 63/M Neuralgic pain in legs, Perivascular infiltrate of
(1961)1
leg weakness,
lymphoid and scattered plasma
atrophy,
cells, less-intense meningeal
preterminal clonic
infiltrate; perivascular
spasms, coma
accumulation of plasma-like
substance; scattered
lymphocytic infiltration of sciatic
nerve
Arias et al.
68/M Cognitive impairment, Not reported
(2004)2
apraxia of gait, urinary
incontinence;
dysarthria, bilateral
Babinski sign, frontal
release signs
Bhatti et al.
(2005)3
Bing and Neel
(1936)4
Bing and Neel
(1936)4
Bing et al.
(1937)5
Diagnostic data
Imaging
Not reported
Not reported
CT with multiple
CSF: WBC 6/l (“lymphoid
cells”), protein 0.62 g/l, glucose hypodensities in white
matter; MRI with
normal
multiple hyperintense
areas on T2/FLAIR,
DWI (ADC not
shown), ‘irregular’
enhancement
CSF cytology and flow cytometry Atrophy, dilated
positive for neoplastic LP cells ventricles (no contrast
given)
61/F Severe headache,
Not reported
bilateral sixth nerve
palsy, episodic
confusion; weeks later
sudden onset of left
hemiparesis and
dysarthria
36/F Rapid onset of
Sparse perivascular and
CSF: mild pleocytosis, protein
weakness in arms and meningeal round-cell infiltration 1.5–1.6 g/l
legs, aphonia,
of cauda equina, spinal cord,
sensation preserved; medulla, pons (arrangement
preterminal severe
resembling “other chronic
headaches, vomiting inflammatory changes”)
59/F Dizziness, flickering Demyelination of spinal cord and Not reported
before the eyes,
cauda equina; round-cell
tingling/numbness in infiltration around a single vessel
fingertips
in medulla
57/F Fatigue, depression, Extensive ‘inflammatory’
CSF: lymphocytic pleocytosis,
apathy; diffuse
changes in nerve roots,
protein 1.8–2.0 g/l
pareses (antigravity meninges, spinal cord and brain
strength), bilateral
Babinski sign
Pathogenetic
mechanism
Nonspecific IgM
deposition,
perivascular infiltrate
Corroborating
data/remarks
Morphologic autopsy
data
Perivascular/
CSF LM morphological
parenchymal infiltrate, analysis
LM infiltrate
LM infiltration
Positive CSF flow
cytometry
Not reported
Perivascular infiltrate Pathogenesis of
neurological syndrome
unclear (acute
inflammatory
neuropathy?)
Not reported
Perivascular infiltrate Minimal neurological
symptoms
Not reported
Perivascular/LM
infiltrate
Morphologic autopsy
data
Civit et al.
(1997)6
70/M Focal motor seizure
Delgado et al.
(2002)7
72/M Weakness, tingling left Not reported
arm
Donix et al.
(2007)8
54/M 9 months of nonfluent Not reported
aphasia; insidious
onset, slow
progression
60/M Seizures with visual Not reported
hallucinations,
cognitive decline,
cerebellar ataxia,
hiccoughs, diplopia;
cogwheel rigidity in
right arm, right
Babinski sign
Hochberg
(unpublished
data)
Hug et al.
(2004)9
Imai et al.
(1995)10
Liberato et al.
(2003)11
Not reported
Right frontoparietal mass with
infiltration of bone, dura LM,
Virchow–Robin spaces, and
cortex; biopsy: CD20+, CD40+,
IgM+, kappa/lambda+; IgH gene
rearrangement clonal
Brain biopsy: lymphomatous
infiltration (mostly perivascular)
Head CT: convexParenchymal/
shaped dural based dural/LM infiltration
mass with contiguous (mass)
involvement of
overlying bone
Faintly enhancing
mass in right basal
ganglia
CSF with abnormal
Numerous T2-positive
lymphocytoid cells with multiple lesions in centrum
mitoses
semiovale
Not reported
65/M Personality change, Not reported
CSF: WBC 60/l, protein 8.45
dysinhibition, frontal
g/l; IgH gene rearrangement
release signs, gait
analysis showed clonal B-cell
problems; left ataxia,
population
dysdiadochokinesis
65/F Confusion, memory Monoclonal plasmacytoid cells in Brain biopsy: infiltration of
loss
left frontal lobe
neoplastic cells (mature
plasmacytoid cells) positive for
IgM and lambda light chain;
immature lymphocytes in
Virchow–Robin spaces negative
for these markers
65/M Lhermitte’s sign
Not reported
IgM 13 g/l, blood viscosity 1.8 s,
initially, then
marrow with lymphoplasmaworsening gait,
cytoid aggregates, CSF protein
stiffness, lower1.06 g/l, WBC 27/l (86%
extremity
lymphocytes) 2 microglobulin
paresthesias, upper22mg/l and oligoclonal bands;
extremity tremor.
negative cytology;
Slowly progressive
immunofixation with faint IgMmyelopathy
kappa band
Parenchymal
infiltration (mass)
LM infiltrate;
perivascular/
parenchymal infiltrate?
Immunohisto-chemistry,
IgH gene rearrangement
analysis of brain tumor
Diffuse lymphomatous
infiltration on brain
biopsy
Morphologic CSF
analysis
Punctate and
Perivascular/
coalescent white
parenchymal infiltrate
matter changes (T2
hyperintense) of both
cerebellar
hemispheres, left
ventral pons, occipital
lobes, left basal
ganglia and thalamus
CT: ventriculo-megaly, LM infiltrate
old ischemic infarct in
right medial thalamus
Improvement after
plasmapheresis and
rituximab
MRI: high-intensity
Parenchymal infiltrate
area on T2-weighted
images in the left
frontal lobe extending
to the corpus
callosum: positive
enhancement
T2 hyperintensity of Parenchymal
entire spinal cord,
infiltration
slight cord
enlargement, small
focus of enhancement
at C2, resolution after
treatment; brain MRI
showed periventricular
white matter changes
“Monoclonal proliferation
was confirmed by
Southern blot analysis”
Clonal IgH gene
rearrangement in CSF
but comparison with
bone marrow not done
Absence of LM
neoplastic cells, spinal
cord enlargement on
MRI with resolution after
therapy, elevated IgM
index in CSF
Logothetis et
al. (1960)12
54/M Asymptomatic from
cerebral lesions found
on autopsy;
secondarily
generalized focal
motor seizures with
postictal right
hemiparesis and
expressive aphasia;
paraparesis from prior
spinal cord infarction
Massengo et
67/F Difficulty walking
al. (2003)13
(ataxic gait, pyramidal
signs), urinary
urgency/incontinence,
sensory loss in legs
Monteiro et al. 74/? 3 weeks of
(1975)14
hemiparesis,
confusion, rigidity and
coma
Monteiro et al. 65/? Peripheral
(1975)14
neuropathy,
Raynaud’s
phenomenon;
disorientation and
coma
Monteiro et al. 69/? Disorientation, coma
(1975)14
Perivascular lymphocytic
Not reported
infiltrate in upper pons, ischemic
myelomalacia in lumbosacral
cord; hemispheres without
pathology; left-upper-quadrant
mass attached to tail of
pancreas, probable systemic
transformation to large-cell
lymphoma
Not reported
Perivascular infiltration Morphologic autopsy
data
Not reported
T2-positive central
cervical spinal cord;
LM enhancement of
lumbar cord, cauda
equine
Not reported
Perivascular/
Positive CSF flow
parenchymal
cytometry
infiltrate?/LM infiltrate
Not reported
Perivascular infiltrate, Morphologic autopsy
LM infiltrate
data
Not reported
Perivascular/
Morphologic autopsy
parenchymal infiltrate data
Not reported
Nonspecific IgM
CSF showed nonspecific
deposition,
increase in protein, no
perivascular infiltrate cells
CSF: WBC 39/l (96%
lymphocytes), flow cytometry:
CD19+, CD20+, CD5–; IgM
0.0999 g/l
Perivascular lymphocytic
Not reported
infiltrate in substantia nigra and
leptomeninges; gliosis in
thalamus and dentate nuclei
Widespread perivascular and
Not reported
LM lymphocytic infiltrate
Dense lymphocytic perivascular Not reported
infiltration in cerebral cortex and
brainstem; massive
accumulation in floor of fourth
ventricle; parenchymal infiltration
in optic tract and hypothalamus
Scheithauer et 56/M 8 months of
Patchy cerebral demyelination, Not reported
al. (1984)15
paresthesia, left arm axonal degeneration,
weakness, tremor of perivascular lymphocytes,
left arm and leg,
macroglobulin permeation to
positive left Babinski white matter (mostly IgM kappa.
sign; later had
electron microscopy showed
symptoms of
inclusions suggestive of
depression, syncope cryoglobulins in macrophages;
and dysphagia
scant lymphoplasmacytic
meningeal infiltrate
Perivascular infiltrate, Morphologic autopsy
LM infiltrate
data
Shimizu et al.
(1993)16
68/F Confusion, dysnomia, Not reported
expressive aphasia
Tommasi et al. 54/F 15 days of ocular
(1966)17
paresis, frontal
release signs,
decreased intellect,
somnolence; later
seizure and coma
Wanner and
51/M Depression, severe
Siebenmann
back pain, acute
(1957)18
paraparesis,
meningeal signs,
delirium
Welch et al.
(2002)18
82/M
Zollinger
(1958)20
71/M
Zollinger
(1958)20
66/F
Zollinger
(1958)20
72/M
Perivascular lymphocytic
infiltrates in brainstem,
cerebellum, leptomeninges and
peripheral nerves
Left frontal lobe mass biopsy:
lymphocytic, LP, plasma cell
infiltrate (lambda-light-chainrestricted) in Virchow–Robin
spaces, surrounding cerebral
parenchyma and vessel wall;
amorphous material in vessel
wall and adjacent brain
parenchyma
Not reported
Homogeneously
enhancing mass in
deep white matter of
left frontal lobe
Nonspecific IgM
deposition,
perivascular/
parenchymal/LM
infiltrate
Not reported
Perivascular infiltrate, Morphologic autopsy
LM infiltrate
data
Diffuse cerebral edema,
Cryoglobulin+; CSF: mild
Not reported
purpura, perivascular
pleocytosis, protein normal,
lymphocytic infiltrate (probably relative increase in gamma
neoplastic) and proteinaceous globulins
extravasation; compression
fracture of T9 and L1; subdural
and subarachnoid hemorrhage
at level of cauda equina
Cognitive decline over 2x2x1 cm lesion in right centrum CSF: mild increased protein,
Diffuse bilateral T22 months, confusion, semiovale; prominent
cytology negative, Epstein–Barr- positive lesions in
irritability
perivascular ‘large-cell’ LP
virus-negative; brain biopsy
centrum semiovale,
infiltrate (CD20+, IgM+, kappa- nondiagnostic
some faintly
restricted), diffuse involvement
enhancing; diffuse
of LM, minimal invasion of
dural enhancement,
neuropil
bilateral subdural fluid
collections
Not reported
Perivascular lymphocytic and
Not reported
Not reported
plasma cell infiltrate in
leptomeninges and brain;
atrophy, hydrocephalus ex
vacuo
Polyneuropathy
Lymphocyte, plasma cell
Not reported
Not reported
infiltrates in leptomeninges and
perivascular space in brain
Not reported
Lymphocytic and plasma cell
Not reported
Not reported
infiltrates in brain
Immunohisto- chemistry:
brain mass showed IgM
lambda restriction (as
was the systemic clone
as shown by serum
protein electrophoresis
with immunofixation
Nonspecific IgM
Autopsy findings;
deposition,
multiple myeloma with
perivascular infiltrate macroglobulinemia;
preterminal
hyperviscosity syndrome
Perivascular/LM/mini Immunohisto-chemistry
mal parenchymal
infiltrate
Perivascular infiltrate, Morphologic autopsy
LM infiltrate?
data
Perivascular infiltrate Morphologic autopsy
data
Perivascular infiltrate Morphologic autopsy
data
Abbreviations: ADC, apparent diffusion coefficient; CSF, cerebrospinal fluid; DWI, diffusion-weighted imaging; F, female; FLAIR, fluidattenuated inversion recovery; LM, leptomeningeal; LP, lymphoplasmacytoid; M, male; WBC, white blood cells
References
1.
Aarseth S et al. (1961) Macroglobulinaemia Waldenstrom. A case with haemolytic syndrome and involvement of the nervous system.
Acta Med Scand 169: 691–699
2.
Arias M et al. (2004) Rapidly progressing dementia as the presenting symptom of Waldenstrom’s macroglobulinemia: findings from
magnetic resonance imaging of the brain in Bing Neel syndrome. Rev Neurol 38: 640–642
3.
Bhatti MT et al. (2005) Bilateral sixth nerve paresis in the Bing–Neel syndrome. Neurology 64: 576–577
4.
Bing J and Neel A (1936) Two cases of hyperglobulinemia with affection of the central nervous system on a toxi-infection basis. Acta
Med Scand 88: 492–506
5.
Bing J et al. (1937) Reports of a third case of hyperglobulinemia with affection of the central nervous system on a toxi-infectious basis.
Acta Medica Scand 91: 410–427
6.
Civit T et al. (1997) Waldenstrom's macroglobulinemia and cerebral lymphoplasmocytic proliferation: Bing and Neel syndrome. Apropos
of a new case. Neurochirurgie 43: 245–249
7.
Delgado J. et al. (2002) Radiation therapy and combination of cladribine, cyclophosphamide, and prednisone as treatment of Bing–Neel
syndrome: case report and review of the literature. Am J Hematol. 69: 127–131
8.
Donix M et al. (2007) Nonfluent aphasia in a patient with Waldenstrom's macroglobulinemia. Journal of Clinical Neuroscience 14: 601–
603
9.
Hug A et al. (2004) Leptomeningeal tumor cell infiltrations as a first manifestation of an immunocytoma (Waldenstrom's
macroglobulinemia). Nervenarzt 75: 1012–1015
10.
Imai F et al. (1995) Intracerebral infiltration by monoclonal plasmacytoid cells in Waldenstrom's macroglobulinemia—case report.
Neurol Med Chir (Tokyo) 35: 575–579
11.
Liberato B et al. (2003) Myelopathy from Waldenstrom's macroglobulinemia: improvement after rituximab therapy. J Neurooncol 63:
207–211
12.
Logothetis J et al. (1960) Neurologic aspects of Waldenstrom's macroglobulinemia; report of a case. Arch Neurol 3: 564–573
13.
Massengo S et al. (2003) Nervous system lymphoid infiltration in Waldenstrom's macroglobulinemia. A case report. J Neurooncol 62:
353–358
14.
Monteiro PL et al. (1975) Waldenstrom's macroglobulinemia with lymphoproliferative changes in the central nervous system. 4 cases.
Schweiz Arch Neurol Neurochir Psychiatr 116: 59–82
15.
Scheithauer BW et al. (1984) Leukoencephalopathy in Waldenstrom's macroglobulinemia. Immunohistochemical and electron
microscopic observations. J Neuropathol Exp Neurol 43: 408–425
16.
Shimizu K et al. (1993) Importance of central nervous system involvement by neoplastic cells in a patient with Waldenstrom's
macroglobulinemia developing neurologic abnormalities. Acta Haematol 90: 206–208
17.
Tommasi M et al. (1966) Waldenstrom's macroglobulinemia. Lesions of the central nervous system. Ann Anat Pathol (Paris) 11: 309–
313
18.
Wanner J and Siebenmann R (1957) Subacute osteolytic form of Waldenstrom's macroglobulinemia with plasma cell leukemia. Schweiz
Med Wochenschr 87: 1243–1246
19.
Welch D et al. (2002) Pathologic quiz case. A man with long-standing monoclonal gammopathy and new onset of confusion. Central
nervous system involvement by Waldenstrom macroglobulinemia-Bing-Neel syndrome. Arch Pathol Lab Med 126: 1243–1244
20.
Zollinger HU (1958) Pathological anatomy of Waldenstrom's macroglobulinemia. Helv Med Acta 25: 153–183